Crystalline forms of nicotinoyl ribosides, modified derivatives thereof, and phosphorylated analogs thereof, and methods of preparation thereof

ABSTRACT

The present disclosure provides novel crystalline forms of nicotinoyl riboside compounds or derivatives of formula (I): 
                         
wherein X − , Z 1 , Z 2 , n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are described herein, modified derivatives thereof, and phosphorylated analogs thereof, or salts, solvates, or prodrugs thereof; and methods of preparation thereof.

This application claims the benefit of U.S. Provisional Application No.62/420,737, filed on Nov. 11, 2016, and U.S. Provisional Application No.62/558,073, filed on Sep. 13, 2017. The disclosures of these priorapplications are incorporated herein by reference in their entiretiesfor all purposes.

TECHNICAL FIELD

The present disclosure relates to synthetic processes for thepreparation of nicotinoyl ribosides and reduced nicotinoyl ribosides,modified derivatives thereof, phosphorylated analogs thereof, andadenylyl dinucleotide conjugates thereof, the synthetic processescomprising processing of reagents by solvent-based processes,liquid-assisted mixing, milling, grinding, solvent-assisted grinding,and/or extrusion, and crystalline forms of nicotinamide riboside, inparticular, nicotinamide riboside chloride, derivatives thereof,crystalline forms of nicotinic acid riboside, derivatives thereof, andcrystalline forms of nicotinamide mononucleotide, and derivativesthereof.

BACKGROUND

The dietary vitamin B3, which encompasses nicotinamide (“Nam” or “NM”),nicotinic acid (“NA”), and nicotinamide riboside (“NR”), is a precursorto the coenzyme nicotinamide adenine dinucleotide (“NAD⁺”), itsphosphorylated parent (“NADP⁺” or “NAD(P)⁺”), and their respectivereduced forms (“NADH” and “NADPH,” respectively). Once convertedintracellularly to NAD(P)⁺ and NAD(P)H, vitamin B3 metabolites are usedas co-substrates in multiple intracellular protein modificationprocesses, which control numerous essential signaling events (e.g.,adenosine diphosphate ribosylation and deacetylation), and as cofactorsin over 400 redox enzymatic reactions, thus controlling metabolism. Thisis demonstrated by a range of metabolic endpoints, which include thedeacylation of key regulatory metabolic enzymes, resulting in therestoration of mitochondrial activity and oxygen consumption.Critically, mitochondrial dysfunction and cellular impairment have beencorrelated to the depletion of the NAD(P)(H)-cofactor pool, when theNAD(P)(H)-cofactor pool is present in sub-optimal intracellularconcentrations. Vitamin B3 deficiency yields to evidenced compromisedcellular activity through NAD(P)⁺ depletion, and the beneficial effectof additional NAD(P)⁺ bioavailability through NA, Nam, NR, andnicotinamide mononucleotide (“NMN”) supplementation is primarilyobserved in cells and tissues where metabolism and mitochondrialfunction have been compromised.

Despite extensive optimization of solution-based methodologies over manyyears for nucleotide preparation, difficulties and issues remain in thesyntheses of nicotinoyl ribosides, the monophosphorylation of activehydroxyl groups thereof, and subsequent conjugation thereof, withrespect to low yields and product stability and isolation from polarsolvents. The current methodologies are also plagued by atom and energyinefficiency due, for example, to the use of large solvent excesses andthe need for temperature-controlled reaction conditions.

The reported syntheses of nicotinamide riboside (NR) are becoming morescalable, but use corrosive and expensive reagents, and lengthydeprotection steps, and thus still display batch-to-batch qualityvariation, thereby presenting difficulties in maintaining goodstandards.

Partially protected nucleosides and nucleotides have found broad-rangingapplication in order to achieve improved bioavailability of thenucleoside and nucleotide parents. Such partial protection includeshydroxyl modifications with ester, carboxylate, and acetyl groups, inaddition to the introduction of hydrolyzable phosphoramidate or mixedanhydride modification of the phosphate monoesters in the form ofProtides and CycloSal derivatives. While the former type of protectionhas become more scalable, the modifications at the phosphorus centerremain difficult to accomplish at scale, particularly on nucleosidicentities that are highly sensitive to changes in pH and that are readilydegraded by heat.

Reduced nicotinamide riboside (“NRH”) has been consistently shown to bemore efficient at increasing intracellular NAD⁺ levels, and surpassesnicotinamide riboside (NR) in that respect. While physiological andpotentially therapeutic roles have not yet been examined due to a lackof material accessible in sufficient quantities for broad-rangingstudies, it is anticipated that the phosphorylated forms of NRH andreduced nicotinic acid riboside (“NARH”), or derivatives thereof, couldalso have similar NAD⁺-boosting capacities.

The reported syntheses of reduced nicotinamide riboside (NRH) arebecoming more widely available but remain conducted on small scales,using corrosive and expensive reagents, and lengthy deprotection steps,and thus still display batch-to-batch quality variation, therebypresenting difficulties in maintaining good standards. In the currentdescription, reduced nicotinamide riboside (NRH) generally refers to“reduced pyridine” nucleus, more specifically, the 1,4-dihydropyridinecompounds.

Synthetically, the preparation of 5′-nucleotides remains time-consuming,atom-inefficient, and costly, due to the need for numerous protectionand deprotection steps. In these preparation methods, thechlorodialkylphosphate, tetraalkylpyrophosphate, chlorophosphite, orphosphoramidite reagents required are also expensive starting materialsby virtue of their chemical functionalization and chemical instability,and therefore, consequently associated synthetic difficulties.Phosphorylation reaction conditions are difficult to control and oftenuse non-approved or toxic organic solvents, thus limiting the market ofthe manufactured compounds.

One known alternative approach to the protection/deprotection method isto use phosphorus oxychloride (P(O)Cl₃) (i.e., Yoshikawa conditions),however there are still drawbacks to this method, as follows. While notbeing bound by theory, in this method, polar trialkyl phosphatesolvents, such as P(O)(OMe)₃, are used in a large excess, which arebelieved to enhance reaction rates while limiting the undesirablereactivity of P(O)Cl₃ as a chlorinating agent. Thus, it is believed thatuse of excess P(O)Cl₃/P(O)(OR)₃ is a better combination for thechemoselective 5′-O-phosphorylation of unprotected ribosides. However,the use of trialkyl phosphate solvents, such as P(O)(OMe)₃, precludestheir implementation for the preparation of materials for eventual humanuse, as this class of solvent is highly toxic (known carcinogen,non-GRAS approved) and is difficult to remove from the final polarproducts. See M. Yoshikawa et al., Studies of Phosphorylation. III.Selective Phosphorylation of Unprotected Nucleosides, 42 BULL. CHEM.SOC. JAPAN 3505 (1969); Jaemoon Lee et al., A chemical synthesis ofnicotinamide adenine dinucleotide (NAD+), CHEM. COMMUN. 729 (1999); eachof which is incorporated by reference herein in its entirety.

Nicotinamide adenine dinucleotide (NAD⁺) remains an expensive cofactor,and its commercial availability is simply limited by its complexchemical nature and the highly reactive pyrophosphate bond, which ischallenging to form at scale.

Nicotinoyl ribosides such as nicotinamide riboside (NR) and nicotinicacid riboside (“NAR”), nicotinamide mononucleotide (NMN), and NAD⁺ areviewed as useful bioavailable precursors of the NAD(P)(H) pool to combatand treat a broad range of non-communicable diseases, in particularthose associated with mitochondrial dysfunction and impaired cellularmetabolism. Optimizing the large-scale syntheses of these vitamin B3derivatives is therefore highly valuable to make these compounds morewidely available to society both in terms of nutraceutical andpharmaceutical entities.

Reduced nicotinoyl ribosides, such as reduced nicotinamide riboside(NRH), reduced nicotinic acid riboside (NARH), reduced nicotinamidemononucleotide (“NMNH”), reduced nicotinic acid mononucleotide(“NaMNH”), and reduced nicotinamide adenine dinucleotide (“NADH”) areviewed as useful bioavailable precursors of the NAD(P)(H) pool to combatand treat a broad range of non-communicable diseases, in particularthose associated with mitochondrial dysfunction and impaired cellularmetabolism. Optimizing the large-scale syntheses of these vitamin B3derivatives is therefore highly valuable to make these compounds morewidely available to society, both in terms of nutraceutical andpharmaceutical entities.

Crystalline forms of useful molecules can have advantageous propertiesrelative to the respective amorphous forms of such molecules. Forexample, crystal forms are often easier to handle and process, forexample, when preparing compositions that include the crystal forms.Crystalline forms typically have greater storage stability and are moreamenable to purification. The use of a crystalline form of apharmaceutically useful compound can also improve the performancecharacteristics of a pharmaceutical product that includes the compound.Obtaining the crystalline form also serves to enlarge the repertoire ofmaterials that formulation scientists have available for formulationoptimization, for example by providing a product with differentproperties, e.g., better processing or handling characteristics,improved dissolution profile, or improved shelf-life.

WO 2016/014927 A2, incorporated by reference herein in its entirety,describes crystalline forms of nicotinamide riboside, including a Form Iof nicotinamide riboside chloride. Also disclosed are pharmaceuticalcompositions comprising the crystalline Form I of nicotinamide ribosidechloride, and methods of producing such pharmaceutical compositions.

WO 2016/144660 A1, incorporated by reference herein in its entirety,describes crystalline forms of nicotinamide riboside, including a FormII of nicotinamide riboside chloride. Also disclosed are pharmaceuticalcompositions comprising the crystalline Form II of nicotinamide ribosidechloride, and methods of producing such pharmaceutical compositions.

In view of the above, there is a need for processes that areatom-efficient in terms of reagent and solvent equivalency, that bypassthe need for polar, non-GRAS (“generally recognized as safe”) solvents,that are versatile in terms of limitations associated with solubilityand reagent mixing, that are time- and energy-efficient, and thatprovide efficient, practical, and scalable methods for the preparationof nicotinoyl ribosides, reduced nicotinoyl ribosides, modifiedderivatives thereof, phosphorylated analogs thereof, and adenylyldinucleotide conjugates thereof.

In view of the above, there is a need for novel crystalline forms ofnicotinoyl ribosides, reduced nicotinoyl ribosides, modified derivativesthereof, phosphorylated analogs thereof, and adenylyl dinucleotideconjugates thereof.

SUMMARY OF THE INVENTION

In an embodiment, the present disclosure relates to a synthetic sequencethat enables the efficient production of nicotinoyl ribosides,derivatives thereof, phosphorylated analogs thereof, and adenylyldinucleotide conjugates thereof, or salts, solvates, or prodrugsthereof, via processes that are enabled by the processing of reagents byliquid-assisted mixing, grinding, milling, and/or extrusion.

In another embodiment, the present disclosure relates to a syntheticsequence that enables the efficient production of reduced nicotinoylribosides, derivatives thereof, phosphorylated analogs thereof, andadenylyl dinucleotide conjugates thereof, or salts, solvates, orprodrugs thereof, via processes that are enabled by the processing ofreagents by liquid-assisted mixing, grinding, milling, and/or extrusion.

In yet another embodiment, the present disclosure relates to scalablemethods of preparation of nicotinamide riboside (NR) and nicotinic acidriboside (NAR), and derivatives thereof, or salts, solvates, or prodrugsthereof, by liquid assisted mixing and/or extrusion.

In yet another embodiment, the present disclosure relates to scalablemethods of preparation of reduced nicotinamide riboside (NRH) andreduced nicotinic acid riboside (NARH), and derivatives thereof, orsalts, solvates, or prodrugs thereof, by liquid-assisted mixing,grinding, and/or extrusion.

In yet another embodiment, the present disclosure relates to scalablemethods of preparation of nicotinamide riboside triacetate (“NRTA”) andnicotinic acid riboside triacetate (“NARTA”), and derivatives thereof,or salts, solvates, or prodrugs thereof, by liquid-assisted mixing,grinding, and/or extrusion.

In yet another embodiment, the present disclosure relates to scalablemethods of preparation of reduced nicotinamide riboside triacetate(“NRH-TA”) and reduced nicotinic acid riboside triacetate (“NARH-TA”),and derivatives thereof, or salts, solvates, or prodrugs thereof, bybiphasic liquid-assisted mixing, grinding, and/or extrusion.

In yet another embodiment, the present disclosure relates to batch andsemi-continuous processes that enable the production of nicotinamideriboside (NR) and nicotinic acid riboside (NAR), and triacetatederivatives thereof, or salts, solvates, or prodrugs thereof, wherebythe use of solvents is kept to a minimum, and whereby conversion andreaction times are optimized by the use of sealed conditions, continuousliquid-liquid extraction, and/or mechanochemistry, and an optimizedpurification sequence.

In yet another embodiment, the present disclosure relates to batch andsemi-continuous processes that enable the production of reducednicotinamide riboside (NRH) and reduced nicotinic acid riboside (NARH),and triacetate derivatives thereof, or salts, solvates, or prodrugsthereof, wherein the use of solvents is kept to a minimum, and wherebyconversion and reaction times are optimized by the use of sealedconditions, continuous liquid-liquid extraction, and/ormechanochemistry, and an optimized purification sequence.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinamide riboside (NR), including, but not limited to, aForm I of nicotinamide riboside chloride (“NR-Cl”), and methods ofpreparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinamide riboside (NR), including, but not limited to, a“NR methanolate Form II” of nicotinamide riboside chloride (NR-Cl), andmethods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinic acid riboside (NAR), including, but not limited to, a“Form I” of nicotinic acid riboside (NAR), and methods of preparationthereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinamide riboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-nicotinamide, “NRtriacetate,” or “NRTA”), including, but not limited to, a “Form I” ofnicotinamide riboside triacetate (NRTA) chloride, and methods ofpreparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinic acid riboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-nicotinic acid, “NARtriacetate,” or “NARTA”), including, but not limited to, a “Form I” ofnicotinic acid riboside triacetate (NARTA), and methods of preparationthereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinamide mononucleotide (“NMN”), including, but not limitedto, a “Form III” of nicotinamide mononucleotide (NMN), and methods ofpreparation thereof. In yet another embodiment, the present disclosurerelates to an amorphous solid form of nicotinamide mononucleotide (NMN),and methods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinamide mononucleotide (NMN), including, but not limitedto, a “Form IV” of nicotinamide mononucleotide (NMN), and methods ofpreparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of compounds or derivatives having formula (IV), or salts,solvates, or prodrugs thereof, and methods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of compounds or derivatives having formula (IV-H), or salts,solvates, or prodrugs thereof, and methods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of compounds or derivatives having formula (V), or salts,solvates, or prodrugs thereof, and methods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of compounds or derivatives having formula (VI), or salts,solvates, or prodrugs thereof, and methods of preparation thereof.

In an embodiment, the present disclosure provides a novel crystallineForm I of nicotinic acid riboside (NAR), according to formula (VIII):

In another embodiment, the above crystalline Form I can be characterizedby a powder X-ray diffraction pattern having peaks at 19.2, 21.6, and26.4 degrees two theta±0.2 degrees two theta. In yet another embodiment,the above crystalline Form I can be characterized by a powder X-raydiffraction pattern having peaks at 15.7, 19.2, 21.6, 26.4, and 28.9degrees two theta±0.2 degrees two theta. In yet another embodiment, theabove crystalline Form I can be characterized by a powder X-raydiffraction pattern having peaks substantially as shown in FIG. 17.

In yet another embodiment, the above crystalline Form I can be preparedby a method that can include the steps of:

(a) dissolving the compound or derivative having formula (VIII), or saltor solvate thereof, in a volume of methanol; (b) adding a volume ofacetone, of an equal volume to the volume of methanol, to the compoundor derivative having formula (VIII), or salt or solvate thereof, in thevolume of methanol; (c) precipitating the crystalline Form I; and (d)isolating the crystalline Form I.

In yet another embodiment, the above crystalline Form I can be preparedby a method that can further include the steps of:

(a1) providing a compound or derivative having formula (1a), or a saltthereof:

wherein Z² is oxygen;

n is 0;

R¹ is hydrogen;

wherein the compound or derivative having formula (1a) may optionallytake the form of the carboxylate anion conjugate base species of thecompound or derivative having formula (1a), further optionallyassociated with a positively charged counterion selected from the groupconsisting of calcium, magnesium, potassium, sodium, zinc, and ammoniumcations;

each of R², R³, R⁴, and R⁵ is hydrogen;

(a2) treating the compound or derivative having formula (1a), or saltthereof, with excess trimethylsilylating reagent(s), so as to produce acompound or derivative having formula (1a), or salt thereof, wherein R¹is a TMS group; (a3) removing the trimethylsilylating reagent(s); (a4)treating the compound or derivative having formula (1a), or saltthereof, wherein R¹ is a TMS group, with a molar equivalent amount of acompound or derivative having formula (2), or a salt thereof, and amolar equivalent amount of TMSOTf, in an organic solvent co-reagent:

wherein X′ is selected from the group consisting of fluoro, chloro,bromo, iodo, HCO₂, acetoxy, propionoxy, butyroxy, glutamyloxy,aspartyloxy, ascorbyloxy, benzoxy, HOCO₂, citryloxy, carbamyloxy,gluconyloxy, lactyloxy, succinyloxy, sulfoxy, trifluoromethanesulfoxy,trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy;

each of R⁶, R⁷, and R⁸ is —C(O)R′;

R′ is methyl;

(a5) processing the compound or derivative having formula (1a), or saltthereof, wherein R¹ is a TMS group, the compound or derivative havingformula (2), or salt thereof, the TMSOTf, and the organic solventco-reagent, so as to produce a compound or derivative having formula(1a), or salt or solvate thereof, wherein R¹ is a TMS group; (a6) addingwater to, optionally, the compound or derivative having formula (1a), orsalt thereof, wherein R¹ is a TMS group, optionally, the compound orderivative having formula (2), or salt thereof, optionally, the TMSOTf,the organic solvent co-reagent, and the compound or derivative havingformula (Ia), or salt or solvate thereof, optionally wherein R¹ is a TMSgroup; (a7) isolating the compound or derivative having formula (Ia), orsalt or solvate thereof; (a8) dissolving the compound or derivativehaving formula (Ia), or salt or solvate thereof, in methanol, in a gaspressure tube; (a9) cooling the solution of the compound or derivativehaving formula (Ia), or salt or solvate thereof, in methanol, to −78°C.; (a10) bubbling ammonia gas into the solution of the compound orderivative having formula (Ia), or salt or solvate thereof, in methanol;(a11) sealing the pressure tube; (a12) raising the temperature to −20°C.; (a13) cooling the pressure tube at −20° C. for about 12 hours toabout 4 days, so as to produce the compound or derivative having formula(VIII), or salt or solvate thereof; (a14) unsealing the gas pressuretube; and (a15) isolating the compound or derivative having formula(VIII), or salt or solvate thereof; wherein the steps (a1) to (a15) areperformed sequentially, before step (a).

In yet another embodiment, the processing of step (a5) of the abovemethod can be selected from the group consisting of batch processing,liquid-assisted mixing, milling, grinding, and extruding.

In an embodiment, the present disclosure provides a novel crystallineForm I of nicotinamide riboside triacetate (NRTA) chloride, according toformula (IX):

In another embodiment, the above crystalline Form I can be characterizedby a powder X-ray diffraction pattern having peaks at 19.6, 22.1, and26.6 degrees two theta±0.2 degrees two theta. In yet another embodiment,the above crystalline Form I can be characterized by a powder X-raydiffraction pattern having peaks at 9.8, 19.2, 19.6, 22.1, and 26.6degrees two theta±0.2 degrees two theta. In yet another embodiment, theabove crystalline Form I can be characterized by a powder x-raydiffraction pattern substantially as shown in FIG. 18.

In yet another embodiment, the above crystalline Form I can be preparedby a method that can include the steps of:

(a) adding a volume of acetonitrile to the compound or derivative havingformula (IX), or salt or solvate thereof, at room temperature, so as todissolve the compound or derivative having formula (IX), or salt orsolvate thereof, in the volume of acetonitrile; (b) adding a volume ofacetone, which is at least equal in volume to the volume ofacetonitrile, to the solution of the compound or derivative havingformula (IX), or salt or solvate thereof, so as to precipitate thecrystalline Form I; and (c) isolating the crystalline Form I.

In yet another embodiment, the above crystalline Form I can be preparedby a method that can further include the steps of:

(a) providing a compound or derivative having formula (2), or a saltthereof;

wherein X′ is selected from the group consisting of fluoro, chloro,bromo, iodo, HCO₂, acetoxy, propionoxy, butyroxy, glutamyloxy,aspartyloxy, ascorbyloxy, benzoxy, HOCO₂, citryloxy, carbamyloxy,gluconyloxy, lactyloxy, succinyloxy, sulfoxy, trifluoromethanesulfoxy,trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy;

each of R⁶, R⁷, and R⁸ is —C(O)R′;

R′ is methyl;

(a2) treating the compound or derivative having formula (2), or saltthereof, with a molar equivalent amount of a compound or derivativehaving formula (1a), or a salt thereof, and a molar equivalent amount ofTMSOTf:

wherein Z² is NH;

n is 0;

R¹ is hydrogen;

each of R², R³, R⁴, and R⁵ is hydrogen;

(a3) processing the compound or derivative having formula (2), or saltthereof, the compound or derivative having formula (1a), or saltthereof, and TMSOTf, so as to produce the compound or derivative havingformula (IX), or salt or solvate thereof; and (a4) isolating thecompound or derivative having formula (IX), or salt or solvate thereof;wherein the steps (a1) to (a4) are performed sequentially, before step(a).

In yet another embodiment, the processing of step (a3) of the abovemethod can be selected from the group consisting of batch processing,liquid-assisted mixing, milling, grinding, and extruding.

In an embodiment, the present disclosure provides a novel crystallineForm III of nicotinamide mononucleotide (NMN), according to formula(XI):

In another embodiment, the above crystalline Form III can becharacterized by a powder X-ray diffraction pattern having peaks at 7.9,22.9, and 24.8 degrees two theta±0.2 degrees two theta. In yet anotherembodiment, the crystalline Form III can be characterized by a powderX-ray diffraction pattern having peaks at 7.9, 15.6, 17.2, 22.9, and24.8 degrees two theta±0.2 degrees two theta.

In yet another embodiment, the crystalline Form III can be prepared by amethod that can include the steps of:

(a) adding the compound or derivative having formula (XI), or salt orsolvate thereof, to a volume of methanol and water in a 3:2volume:volume ratio at room temperature; (b) stirring the compound orderivative having formula (XI), or salt or solvate thereof, and thevolume of methanol and water so as to dissolve the compound orderivative having formula (XI), or salt or solvate thereof, in thevolume of methanol and water; (c) filtering the solution of the compoundor derivative having formula (XI), or salt or solvate thereof, in thevolume of methanol and water, so as to remove any undissolved solids;(d) adding a volume of acetone to the solution of the compound orderivative having formula (XI), or salt or solvate thereof, in thevolume of methanol and water, wherein the volume of acetone is about 2to about 5 times the combined volume of methanol and water; (e) coolingthe compound or derivative having formula (XI), or salt or solvatethereof, in the volume of acetone and the volume of methanol and water,to −20° C. so as to precipitate the crystalline Form III; (f) isolatingthe crystalline Form III; and (g) drying the crystalline Form III atroom temperature.

In yet another embodiment, the crystalline Form III can be prepared by amethod that can further include the steps of:

(a1) providing a compound or derivative having formula (Ia), or a saltor solvate thereof:

wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻ isselected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

Z² is NH;

n is 0;

R¹ is hydrogen;

each of R², R³, R⁴, and R⁵ is hydrogen;

each of R⁶, R⁷, and R⁸ is hydrogen;

(a2) treating the compound or derivative having formula (Ia-H), or saltor solvate thereof, with a phosphorylating reagent; (a3) processing thecompound or derivative having formula (Ia-H), or salt or solvatethereof, and the phosphorylating reagent, so as to produce the compoundor derivative having formula (XI), or salt or solvate thereof; (a4)adding, optionally, the compound or derivative having formula (XI), orsalt or solvate thereof, optionally, the phosphorylating reagent, andthe compound or derivative having formula (XI), or salt or solvatethereof, to iced water; and (a5) isolating the compound or derivativehaving formula (XI), or salt or solvate thereof; wherein the steps (a1)to (a5) are performed sequentially, before step (a).

In yet another embodiment, the processing of step (a3) of the abovemethod can be selected from the group consisting of batch processing,liquid-assisted grinding, and extruding.

In yet another embodiment, the crystalline Form III can be prepared by amethod that can further include the steps of:

(a1) providing a compound or derivative having formula (Ia), or a saltor solvate thereof:

wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻ isselected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

Z² is NH;

n is 0;

R¹ is hydrogen;

each of R², R³, R⁴, and R⁵ is hydrogen;

each of R⁶, R⁷, and R⁸ is hydrogen;

(a2) treating the compound or derivative having formula (Ia-H), or saltor solvate thereof, with a phosphitylating reagent, and a (0<x≤20) molarequivalent amount of a Brønsted base; (a3) processing the compound orderivative having formula (Ia-H), or salt or solvate thereof, thephosphitylating reagent, and the Brønsted base, so as to produce aphosphitylated analog of the compound or derivative having formula(Ia-H), or a salt or solvate thereof; (a4) adding an oxidizing agentreagent to, optionally, the compound or derivative having formula(Ia-H), or salt or solvate thereof, optionally, the phosphitylatingreagent, optionally, the Brønsted base, and the phosphitylated analog ofthe compound or derivative having formula (Ia-H), or salt or solvatethereof; (a5) processing the oxidizing agent reagent, optionally, thecompound or derivative having formula (Ia-H), or salt or solvatethereof, optionally, the phosphitylating reagent, optionally, theBrønsted base, and the phosphitylated analog of the compound orderivative having formula (Ia-H), or salt or solvate thereof, so as toproduce the compound or derivative having formula (XI), or salt orsolvate thereof; (a6) adding, optionally, the oxidizing agent reagent,optionally, the compound or derivative having formula (Ia-H), or salt orsolvate thereof, optionally, the phosphitylating reagent, optionally,the Brønsted base, optionally, the phosphitylated analog of the compoundor derivative having formula (Ia-H), or salt or solvate thereof, and thecompound or derivative having formula (XI), or salt or solvate thereof,to iced water; and (a7) isolating the compound or derivative havingformula (XI), or salt or solvate thereof; wherein the steps (a1) to (a7)are performed sequentially, before step (a).

In yet another embodiment, the processing of steps (a3) and (a5) of theabove method is each independently selected from the group consisting ofbatch processing, liquid-assisted grinding, and extruding.

In an embodiment, the present disclosure provides a novel crystallineForm IV of nicotinamide mononucleotide (NMN), according to formula (XI):

In another embodiment, the above crystalline Form IV can becharacterized by a powder X-ray diffraction pattern having peaks at 9.6,22.8, and 25.3 degrees two theta±0.2 degrees two theta. In yet anotherembodiment, the crystalline Form IV can be characterized by a powderX-ray diffraction pattern having peaks at 9.6, 16.2, 22.0, 22.8, 25.3,and 25.6 degrees two theta±0.2 degrees two theta.

In yet another embodiment, the crystalline Form IV can be prepared by amethod that can include the steps of:

(a) adding the compound or derivative having formula (XI), or salt orsolvate thereof, to a volume of ethanol and water in a 3:2 volume:volumeratio at room temperature, wherein the compound or derivative havingformula (XI), or salt or solvate thereof, is added in an amount of about200 milligrams per milliliter of the volume of ethanol and water; (b)stirring the compound or derivative having formula (XI), or salt orsolvate thereof, and the volume of ethanol and water so as to dissolvethe compound or derivative having formula (XI), or salt or solvatethereof, in the volume of ethanol and water; (c) filtering the solutionof the compound or derivative having formula (XI), or salt or solvatethereof, in the volume of ethanol and water, so as to remove anyundissolved solids; (d) cooling the compound or derivative havingformula (XI), or salt or solvate thereof, in the volume of ethanol andwater, to −10° C. for about 48 hours so as to precipitate thecrystalline Form IV; (e) isolating the crystalline Form IV; and (g)drying the crystalline Form IV at room temperature.

In yet another embodiment, the crystalline Form IV can be prepared by amethod that can further include the steps of:

(a1) providing a compound or derivative having formula (Ia), or a saltor solvate thereof:

wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻ isselected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

Z² is NH;

n is 0;

R¹ is hydrogen;

each of R², R³, R⁴, and R⁵ is hydrogen;

each of R⁶, R⁷, and R⁸ is hydrogen;

(a2) treating the compound or derivative having formula (Ia-H), or saltor solvate thereof, with a phosphorylating reagent; (a3) processing thecompound or derivative having formula (Ia-H), or salt or solvatethereof, and the phosphorylating reagent, so as to produce the compoundor derivative having formula (XI), or salt or solvate thereof; (a4)adding, optionally, the compound or derivative having formula (XI), orsalt or solvate thereof, optionally, the phosphorylating reagent, andthe compound or derivative having formula (XI), or salt or solvatethereof, to iced water; and (a5) isolating the compound or derivativehaving formula (XI), or salt or solvate thereof; wherein the steps (a1)to (a5) are performed sequentially, before step (a).

In yet another embodiment, the processing of step (a3) of the abovemethod can be selected from the group consisting of batch processing,liquid-assisted grinding, and extruding.

In yet another embodiment, the crystalline Form IV can be prepared by amethod that can further include the steps of:

(a1) providing a compound or derivative having formula (Ia), or a saltor solvate thereof:

wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻ isselected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

Z² is NH;

n is 0;

R¹ is hydrogen;

each of R², R³, R⁴, and R⁵ is hydrogen;

each of R⁶, R⁷, and R⁸ is hydrogen;

(a2) treating the compound or derivative having formula (Ia-H), or saltor solvate thereof, with a phosphitylating reagent, and a (0<x≤20) molarequivalent amount of a Brønsted base; (a3) processing the compound orderivative having formula (Ia-H), or salt or solvate thereof, thephosphitylating reagent, and the Brønsted base, so as to produce aphosphitylated analog of the compound or derivative having formula(Ia-H), or a salt or solvate thereof; (a4) adding an oxidizing agentreagent to, optionally, the compound or derivative having formula(Ia-H), or salt or solvate thereof, optionally, the phosphitylatingreagent, optionally, the Brønsted base, and the phosphitylated analog ofthe compound or derivative having formula (Ia-H), or salt or solvatethereof; (a5) processing the oxidizing agent reagent, optionally, thecompound or derivative having formula (Ia-H), or salt or solvatethereof, optionally, the phosphitylating reagent, optionally, theBrønsted base, and the phosphitylated analog of the compound orderivative having formula (Ia-H), or salt or solvate thereof, so as toproduce the compound or derivative having formula (XI), or salt orsolvate thereof; (a6) adding, optionally, the oxidizing agent reagent,optionally, the compound or derivative having formula (Ia-H), or salt orsolvate thereof, optionally, the phosphitylating reagent, optionally,the Brønsted base, optionally, the phosphitylated analog of the compoundor derivative having formula (Ia-H), or salt or solvate thereof, and thecompound or derivative having formula (XI), or salt or solvate thereof,to iced water; and (a7) isolating the compound or derivative havingformula (XI), or salt or solvate thereof; wherein the steps (a1) to (a7)are performed sequentially, before step (a).

In yet another embodiment, the processing of steps (a3) and (a5) of theabove method is each independently selected from the group consisting ofbatch processing, liquid-assisted grinding, and extruding.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a ¹H NMR spectrum of the reaction product mixture for theprocedure described in Example 1, Part A, performed in accordance withone embodiment of the described method for the preparation of a compoundor derivative having general formula (2) or a salt thereof.

FIG. 2 depicts a ¹H NMR spectrum of the reaction product mixture for theprocedure described in Example 1, Part B, performed in accordance withone embodiment of the described method for the preparation of a compoundor derivative having general formula (I) or a salt, solvate, or prodrugthereof.

FIG. 3 depicts a ¹H NMR spectrum of the reaction product mixture for theprocedure described in Example 1, Part B, performed in accordance withone embodiment of the described method for the preparation of a compoundor derivative having general formula (I) or a salt, solvate, or prodrugthereof, after removal of polar organic solvent co-reagent.

FIG. 4 depicts a ¹H NMR spectrum of the reaction product precipitatedand isolated from the reaction product mixture for the proceduredescribed in Example 1, Part B, performed in accordance with oneembodiment of the described method for the preparation of a compound orderivative having general formula (I) or a salt, solvate, or prodrugthereof.

FIG. 5 depicts a ¹H NMR spectrum of riboside tetraacetate, recycled fromthe reaction product mixture for the procedure described in Example 1,Part A (bottom), as compared to standard for riboside tetraacetate(top), performed in accordance with one embodiment of the describedmethod for the preparation of a compound or derivative having generalformula (2) or a salt thereof.

FIG. 6 depicts a ¹H NMR spectrum of the reaction product isolated fromthe reaction product mixture for the procedure described in Example 1,Part B, performed in accordance with one embodiment of the describedmethod for the preparation of a compound or derivative having generalformula (I) or a salt, solvate, or prodrug thereof.

FIG. 7 depicts a ¹H NMR spectrum of a compound or derivative havinggeneral formula (I), purified subsequent to isolation from the reactionproduct mixture for the procedure described in Example 1, Part B,performed in accordance with one embodiment of the described method forthe preparation of a compound or derivative having general formula (I)or a salt, solvate, or prodrug thereof.

FIG. 8 depicts a comparison of ¹H NMR spectra of a compound orderivative having general formula (I) as starting material (bottom), thereaction product mixture after treatment at low temperature with a baseaddition salt according to the procedure described in Example 1, Part D(middle), performed in accordance with one embodiment of the describedmethod for the preparation of a compound or derivative having generalformula (I-H) or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen, and purified desired product (top).

FIG. 9 depicts a comparison of ¹H NMR spectra of a compound orderivative having general formula (I) as starting material (bottom), thereaction product mixture after treatment at room temperature with a baseaddition salt according to the procedure described in Example 1, Part D(middle), performed in accordance with one embodiment of the describedmethod for the preparation of a compound or derivative having generalformula (I-H) or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen, and purified desired product (top).

FIG. 10 depicts a comparison of ¹H NMR spectra of a compound orderivative having general formula (I) as starting material (bottom), thereaction product mixture after treatment at room temperature with acidaddition at two different concentrations according to the proceduredescribed in Example 1, Part D (middle), performed in accordance withone embodiment of the described method for the preparation of a compoundor derivative having general formula (Ia-H) or a salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, and purifieddesired product (top).

FIG. 11(a) depicts a ¹H NMR spectrum of a product filtrate of a compoundor derivative having general formula (Ia-H), performed in accordancewith one embodiment of the described method for the preparation of acompound or derivative having general formula (Ia-H) or a salt, solvate,or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

FIG. 11(b) depicts a ¹H NMR spectrum of the impurity-containingsupernatant remaining after filtration of the product filtraterepresented by the ¹H NMR spectrum depicted in FIG. 11(a), performed inaccordance with one embodiment of the described method for thepreparation of a compound or derivative having general formula (Ia-H) ora salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen.

FIG. 12 depicts a ¹H NMR spectrum of the reaction mixture, performed inaccordance with one embodiment of the described method for thepreparation of a compound or derivative having general formula (Ia-H),or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, according to the procedure described in Example 1, Part C,wherein reaction was conducted for 10 minutes at 50 RPM.

FIG. 13 depicts a ¹H NMR spectrum of the reaction mixture, performed inaccordance with one embodiment of the described method for thepreparation of a compound or derivative having general formula (Ia-H),or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, according to the procedure described in Example 1, Part C,wherein reaction was conducted for 10 minutes at 100 RPM.

FIG. 14 depicts a ¹H NMR spectrum of the reaction mixture, performed inaccordance with one embodiment of the described method for thepreparation of a compound or derivative having general formula (Ia-H),or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, according to the procedure described in Example 1, Part C,wherein reaction was conducted for 15 minutes at 250 RPM.

FIG. 15 provides an X-ray powder diffraction pattern for the previouslydescribed Form I of crystalline nicotinamide riboside chloride (NR-Cl),the compound having formula (VII), prepared according to an embodimentof the presently disclosed methods for the preparation of a compound orderivative having general formula (Ia-H), or a salt, solvate, or prodrugthereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

FIG. 16 provides an X-ray powder diffraction pattern for the presentlydisclosed NR methanolate Form II of crystalline nicotinamide ribosidechloride (NR-Cl), the compound having formula (VII), prepared accordingto am embodiment of the presently disclosed methods for the preparationof a compound or derivative having general formula (Ia-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

FIG. 17 provides an X-ray powder diffraction pattern for the presentlydisclosed Form I of crystalline nicotinic acid riboside (NAR), thecompound having formula (VIII) prepared according to an embodiment ofthe presently disclosed methods for the preparation of a compound orderivative having general formula (Ia-H), or a salt, solvate, or prodrugthereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

FIG. 18 provides an X-ray powder diffraction pattern for the presentlydisclosed Form I of crystalline nicotinamide riboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-nicotinamide, “NRtriacetate,” or “NRTA”), the compound having formula (IX), preparedaccording to an embodiment of the presently disclosed methods for thepreparation of a compound or derivative having general formula (Ia), ora salt, solvate, or prodrug thereof.

FIG. 19 provides an X-ray powder diffraction pattern for the presentlydisclosed Form I of crystalline nicotinic acid riboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-nicotinic acid, “NARtriacetate,” or “NARTA”), the compound having formula (X), preparedaccording to an embodiment of the presently disclosed methods for thepreparation of a compound or derivative having general formula (Ia), ora salt, solvate, or prodrug thereof.

FIG. 20 provides an X-ray powder diffraction pattern for the presentlydisclosed Form III of crystalline nicotinamide mononucleotide (NMN), thecompound having formula (XI), prepared according to an embodiment of thepresently disclosed methods for the preparation of a compound orderivative having general formula (IIa), or a salt, solvate, or prodrugthereof.

FIG. 21 provides an X-ray powder diffraction pattern for the presentlydisclosed amorphous solid form of nicotinamide mononucleotide (NMN), thecompound having formula (XI), prepared according to an embodiment of thepresently disclosed methods for the preparation of a compound orderivative having general formula (IIa), or a salt, solvate, or prodrugthereof.

FIG. 22 provides a solid state IR spectrum for the presently disclosedNR methanolate Form II of crystalline nicotinamide riboside chloride(NR-Cl), the compound having formula (VII).

FIG. 23 provides a solid state IR spectrum for the presently disclosedForm I of crystalline nicotinic acid riboside (NAR), the compound havingformula (VIII).

FIG. 24 provides a solid state IR spectrum for the presently disclosedForm I of crystalline nicotinamide riboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-nicotinamide, “NRtriacetate,” or “NRTA”), the compound having formula (IX).

FIG. 25 provides a solid state IR spectrum for the presently disclosedForm I of crystalline nicotinic acid riboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-nicotinic acid, “NARtriacetate,” or “NARTA”), the compound having formula (X).

FIG. 26 provides a solid state IR spectrum for the presently disclosedForm III of crystalline nicotinamide mononucleotide (NMN), the compoundhaving formula (XI).

FIG. 27 provides a solid state IR spectrum for the presently disclosedamorphous solid form of nicotinamide mononucleotide (NMN), the compoundhaving formula (XI).

FIG. 28 provides an X-ray powder diffraction pattern for the presentlydisclosed Form IV of crystalline nicotinamide mononucleotide (NMN), thecompound having formula (XI), prepared according to an embodiment of thepresently disclosed methods for the preparation of a compound orderivative having general formula (IIa), or a salt, solvate, or prodrugthereof.

FIG. 29 provides a solid state IR spectrum for the presently disclosedForm IV of crystalline nicotinamide mononucleotide (NMN), the compoundhaving formula (XI).

FIG. 30 provides a DSC thermogram for a sample of the presentlydisclosed crystalline NR methanolate Form II of nicotinamide ribosidechloride that was heated at a rate of 10 K/min.

FIG. 31 provides a DSC thermogram for a sample of the presentlydisclosed Form I of crystalline nicotinamide riboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-nicotinamide, “NRtriacetate,” or “NRTA”), the compound having formula (IX), which washeated at a rate of 10 K/min.

FIG. 32 provides a DSC thermogram for a sample of the presentlydisclosed Form I of crystalline nicotinic acid riboside (NAR), thecompound having formula (VIII), which was heated at a rate of 10 K/min.

FIG. 33 provides a DSC thermogram for a sample of the presentlydisclosed Form I of crystalline nicotinic acid riboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-nicotinic acid, “NARtriacetate,” or “NARTA”), the compound having formula (X), which washeated at a rate of 10 K/min.

FIG. 34 provides a DSC thermogram for a sample of the presentlydisclosed amorphous solid form of nicotinamide mononucleotide (NMN), thecompound having formula (XI), which was heated at a rate of 10 K/min.

FIG. 35 provides a DSC thermogram for a sample of the presentlydisclosed Form III of crystalline nicotinamide mononucleotide (NMN), thecompound having formula (XI), which was heated at a rate of 10 K/min.

FIG. 36 provides a DSC thermogram for a sample of the presentlydisclosed Form IV of crystalline nicotinamide mononucleotide (NMN), thecompound having formula (XI), which was heated at a rate of 10 K/min.

FIG. 37 provides an X-ray powder diffraction pattern for the presentlydisclosed amorphous solid form of reduced nicotinamide riboside (NRH,Compound 9, infra), prepared according to an embodiment of the presentlydisclosed methods for the preparation of a compound or derivative havinggeneral formula (IVa-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen.

FIG. 38 provides an X-ray powder diffraction pattern for the presentlydisclosed amorphous solid form of reduced nicotinic acid riboside (NARH,Compound 10, infra), prepared according to an embodiment of thepresently disclosed methods for the preparation of a compound orderivative having general formula (IVa-H), or a salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

FIG. 39 provides an X-ray powder diffraction pattern for the presentlydisclosed amorphous solid form of crystalline reduced nicotinamideriboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-1,4-dihydronicotinamide,“NRH triacetate,” or “NRH-TA,” Compound 7, infra), prepared according toan embodiment of the presently disclosed methods for the preparation ofa compound or derivative having general formula (IVa), or a salt,solvate, or prodrug thereof.

FIG. 40 provides an X-ray powder diffraction pattern for the presentlydisclosed amorphous solid form of crystalline reduced nicotinic acidtriacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-1,4-dihydronicotinic acid,“NARH triacetate,” or “NARH-TA,” Compound 8, infra), prepared accordingto an embodiment of the presently disclosed methods for the preparationof a compound or derivative having general formula (IVa), or a salt,solvate, or prodrug thereof.

FIG. 41 depicts a comparison of ¹H NMR spectra of reduced nicotinamideriboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-1,4-dihydronicotinamide,“NRH triacetate,” or “NRH-TA,” Compound 7, infra), prepared usingordinary solvent-based laboratory techniques (top), with reducednicotinamide riboside triacetate (NRH-TA), performed in accordance withone embodiment of the described methods for the preparation of acompound or derivative having general formula (IVa), or a salt, solvate,or prodrug thereof (bottom).

FIG. 42 depicts a comparison of ¹H NMR spectra of reduced nicotinic acidriboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-1,4-dihydronicotinic acid,“NARH triacetate,” or “NARH-TA,” Compound 8, infra), prepared usingordinary solvent-based laboratory techniques (top), with reducednicotinic acid riboside triacetate (NARH-TA), performed in accordancewith one embodiment of the described methods for the preparation of acompound or derivative having general formula (IVa), or a salt, solvate,or prodrug thereof (bottom).

FIG. 43 depicts a comparison of ¹H NMR spectra of reduced nicotinamideriboside (1-(beta-D-ribofuranosyl)-1,4-dihydronicotinamide, “NRH,”Compound 9, infra) prepared using ordinary solvent-based laboratorytechniques (top), with reduced nicotinamide riboside (NRH), performed inaccordance with one embodiment of the described methods for thepreparation of a compound or derivative having general formula (IVa-H),or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen (bottom).

FIG. 44 depicts a comparison of ¹H NMR spectra of reduced nicotinic acidriboside (1-beta-D-ribofuranosyl)-1,4-dihydronicotinic acid, “NARH,”Compound 10, infra) prepared using ordinary solvent-based laboratorytechniques (top), with reduced nicotinic acid riboside (NARH), performedin accordance with one embodiment of the described methods for thepreparation of a compound or derivative having general formula (IVa-H),or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen (bottom).

FIG. 45 depicts a ¹⁹F NMR spectrum of product nicotinic acid riboside(NAR), the compound having formula (VIII), prepared according to anembodiment of the described methods for the preparation of a compound orderivative having general formula (Ia-H), or a salt, solvate, or prodrugthereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, showing the absenceof any fluorine shifts corresponding to the absence of anyfluorine-containing species in the product, and wherein the methodincludes the use of a Lewis acid including a trifluoromethanesulfonate(“triflate”) species.

FIG. 46 depicts a ¹⁹F NMR spectrum of product nicotinic acid ribosidetriacetate (NARTA), the compound having formula (X), prepared accordingto an embodiment of the described methods for the preparation of acompound or derivative general having formula (Ia), or a salt, solvate,or prodrug thereof, showing the absence of any fluorine shiftscorresponding to the absence of any fluorine-containing species in theproduct, and wherein the method includes the use of a Lewis acidincluding a trifluoromethanesulfonate (“triflate”) species.

DETAILED DESCRIPTION

In an embodiment, the present disclosure relates to a synthetic sequencethat enables the efficient production of nicotinoyl ribosides, thetriacetates thereof, phosphorylated analogs thereof, and adenylyldinucleotide conjugates thereof, or salts, solvates, or prodrugsthereof, via processes that are enabled by the processing of reagents byliquid-assisted mixing, grinding, milling, and/or extrusion.

In another embodiment, the present disclosure relates to a syntheticsequence that enables the efficient production of reduced nicotinoylribosides, the triacetates thereof, phosphorylated analogs thereof, andadenylyl dinucleotide conjugates thereof, or salts, solvates, orprodrugs thereof, via processes that are enabled by the processing ofreagents by liquid-assisted mixing, grinding, milling, and/or extrusion.

In yet another embodiment, the present disclosure relates to thescalable methods of preparation of nicotinamide riboside (NR) andnicotinic acid riboside (NAR), and derivatives thereof, or salts,solvates, or prodrugs thereof, by liquid-assisted mixing, grinding,and/or extrusion.

In yet another embodiment, the present disclosure relates to thescalable methods of preparation of reduced nicotinamide riboside (NRH)and reduced nicotinic acid riboside (NARH), and derivatives thereof, orsalts, solvates, or prodrugs thereof, by liquid-assisted mixing,grinding, and/or extrusion.

In yet another embodiment, the present disclosure relates to thescalable methods of preparation of reduced nicotinamide ribosidetriacetate (NRH-TA) and reduced nicotinic acid riboside triacetate(NARH-TA), and derivatives thereof, or salts, solvates, or prodrugsthereof, by biphasic liquid-assisted mixing, grinding, and/or extrusion.

In yet another embodiment, the present disclosure relates to the batchprocesses that enable the production of nicotinamide riboside (NR) andnicotinic acid riboside (NAR), or salts, solvates, or prodrugs thereof,whereby the use of solvents in kept to a minimum, and whereby conversionand reaction times are optimized by the use of sealed conditions and/ormechanochemistry, and an optimized purification sequence.

In yet another embodiment, the present disclosure relates to the batchand semi-continuous processes that enable the production of reducednicotinamide riboside (NRH) and reduced nicotinic acid riboside (NARH),and triacetate derivatives thereof, or salts, solvates, or prodrugsthereof, wherein the use of solvents is kept to a minimum, and wherebyconversion and reaction times are optimized by the use of sealedconditions, continuous liquid-liquid extraction, and/ormechanochemistry, and an optimized purification sequence.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinamide riboside (NR), including, but not limited to, aForm I of nicotinamide riboside chloride (“NR-Cl”), and methods ofpreparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinamide riboside (NR), including, but not limited to, a“NR methanolate Form II” of nicotinamide riboside chloride (NR-Cl), andmethods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinic acid riboside (NAR), including, but not limited to, a“Form I” of nicotinic acid riboside (NAR), and methods of preparationthereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinamide riboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-nicotinamide, “NRtriacetate,” or “NRTA”), including, but not limited to, a “Form I” ofnicotinamide riboside triacetate (NRTA) chloride, and methods ofpreparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinic acid riboside triacetate(1-(2′,3′,5′-triacetyl-beta-D-ribofuranosyl)-nicotinic acid, “NARtriacetate,” or “NARTA”), including, but not limited to, a “Form I” ofnicotinic acid riboside triacetate (NARTA), and methods of preparationthereof.

In yet another embodiment, the present disclosure relates to crystallineforms of nicotinamide mononucleotide (“NMN”), including, but not limitedto, a “Form III” of nicotinamide mononucleotide (NMN), and methods ofpreparation thereof. In yet another embodiment, the present disclosurerelates to an amorphous solid form of nicotinamide mononucleotide (NMN),and methods of preparation thereof. In yet another embodiment, thepresent disclosure relates to crystalline forms of nicotinamidemononucleotide (NMN), including, but not limited to, a “Form IV” ofnicotinamide mononucleotide (NMN), and methods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of compounds or derivatives having formula (III), or salts,solvates, or prodrugs thereof, and methods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of compounds or derivatives having formula (IV), or salts,solvates, or prodrugs thereof, and methods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of compounds or derivatives having formula (IV-H), or salts,solvates, or prodrugs thereof, and methods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of compounds or derivatives having formula (V), or salts,solvates, or prodrugs thereof, and methods of preparation thereof.

In yet another embodiment, the present disclosure relates to crystallineforms of compounds or derivatives having formula (VI), or salts,solvates, or prodrugs thereof, and methods of preparation thereof.

In accordance with an embodiment, the present disclosure provides anovel method whereby sealed conditions and/or mechanic forces are usedto minimize solvent quantities, decrease reaction times, increaseoverall conversion, and facilitate product purification in a multistepsynthetic sequence, whereby by-product formation is minimized, andwhereby primarily by-products that can be removed readily by filtrationor evaporation are generated.

Additionally, the methods of the present disclosure address limitationsof existing technologies to produce compounds or derivatives such asnicotinoyl ribosides, reduced nicotinoyl ribosides, the triacetatesthereof, derivatives thereof, phosphorylated analogs thereof, andadenylyl dinucleotide conjugates thereof, or salts, solvates, orprodrugs thereof.

In accordance with one embodiment, the present disclosure provides anovel method for the preparation of compounds or derivatives havingformula (I), or salts, solvates, or prodrugs thereof, such as nicotinoylribosides and their derivatives, and including but not limited to thetriacetylated forms of NR-Cl (nicotinamide riboside chloride salt form)and NAR (nicotinic acid riboside) (compounds or derivatives havingformula (I), wherein R⁶, R⁷, and R⁸ are each acetyl groups), and thefully deprotected forms thereof (compounds or derivatives having formula(I), wherein R⁶, R⁷, and R⁸ are each hydrogens), in commercialquantities. In accordance with such an embodiment, the presentdisclosure provides a novel method whereby mechanic forces and/or sealedconditions are used to minimize solvent and reagent quantities, decreasereaction times, increase overall conversion, and facilitate productpurification in a multistep synthetic sequence, whereby by-productformation is minimized, and whereby primarily by-products that can beremoved readily by filtration or evaporation are generated. Prototypeproduct nicotinoyl riboside compounds include compounds or derivativeshaving formula (I), or salts, solvates, or prodrugs thereof:

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein when X⁻ is absent optionally the counterion is aninternal salt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoicacid (being lactic acid, the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of an unsubstituted monocarboxylic acidselected from formic acid, acetic acid, propionic acid, or butyric acid,being formate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion of ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, substituted carbonate, substitutedglutathione, and substituted glutathione disulfide are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (I) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (I), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —SO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R², R³, R⁴, and R⁵ are each independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂,—C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁶ is selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′,—C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl, substituted orunsubstituted (C₁-C₈)cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitaminB6 ester, choline ester, biotin ester, vitamin A ester, resveratrolester, glutathione ester, glutathione disulfide ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (I), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (1),or salts thereof:

wherein each Z¹ and Z² is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

each R¹ is independently selected from the group consisting of hydrogen,substituted or unsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, m is 1, and n is 0, thecompound or derivative having formula (1) may optionally take the formof the carboxylate anion conjugate base species of the compound orderivative having formula (1), further optionally associated with apositively charged counterion selected from the group consisting ofalkali metal, alkaline earth metal, transition metal, and base additioncations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R², R³, R⁴, and R⁵ are each independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂,—C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (I), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (2),or salts thereof:

wherein X′ is selected from the group consisting of fluoro, chloro,bromo, iodo, HCO₂, acetoxy, propionoxy, butyroxy, glutamyloxy,aspartyloxy, ascorbyloxy, benzoxy, HOCO₂, citryloxy, carbamyloxy,gluconyloxy, lactyloxy, methyl bromo, methyl sulfoxy, nitrate,phosphate, diphosphate, succinyloxy, sulfoxy, trifluoromethanesulfoxy,trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy;

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein when X⁻ is absent optionally the counterion is aninternal salt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoicacid (being lactic acid; the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid selectedfrom formic acid, acetic acid, propionic acid, or butyric acid, beingformate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion of ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, substituted carbonate, substitutedglutathione, and substituted glutathione disulfide are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁶ is selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′,—C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl, substituted orunsubstituted (C₁-C₈)cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitaminB6 ester, choline ester, biotin ester, vitamin A ester, resveratrolester, glutathione ester, glutathione disulfide ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substitutentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with an alternative embodiment, prototype productnicotinoyl riboside compounds include compounds or derivatives havingformula (Ia), or salts, solvates, or prodrugs thereof:

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein when X⁻ is absent optionally the counterion is aninternal salt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoicacid (being lactic acid, the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of an unsubstituted monocarboxylic acidselected from formic acid, acetic acid, propionic acid, or butyric acid,being formate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion of ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, substituted carbonate, substitutedglutathione, and substituted glutathione disulfide are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (Ia) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (Ia), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

each of R², R³, R⁴, and R⁵ is hydrogen;

R⁶ is selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′,—C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl, substituted orunsubstituted (C₁-C₈)cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitaminB6 ester, choline ester, biotin ester, vitamin A ester, resveratrolester, glutathione ester, glutathione disulfide ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (Ia), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (1a),or salts thereof:

wherein Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (1a) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (1a), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester biotinyl; whereinthe substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

each of R², R³, R⁴, and R⁵ is hydrogen;

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (Ia), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (1b),or salts thereof:

wherein each Z¹ and Z² is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

each R¹ is independently selected from the group consisting of hydrogen,substituted or unsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —SO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, m is 1, and n is 0, thecompound or derivative having formula (1b) may optionally take the formof the carboxylate anion conjugate base species of the compound orderivative having formula (1b), further optionally associated with apositively charged counterion selected from the group consisting ofalkali metal, alkaline earth metal, transition metal, and base additioncations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH, —(CH₂)₂C(═O)—NH₂,—(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃, —CH₂CH(CH₃)₂,—(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH, —CH(OH)—CH₃,—CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂, and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester biotinyl; whereinthe substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

each of R², R³, R⁴, and R⁵ is hydrogen;

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (Ia), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (2),or salts thereof:

wherein X′ is selected from the group consisting of fluoro, chloro,bromo, iodo, HCO₂, acetoxy, propionoxy, butyroxy, glutamyloxy,aspartyloxy, ascorbyloxy, benzoxy, HOCO₂, citryloxy, carbamyloxy,gluconyloxy, lactyloxy, methyl bromo, methyl sulfoxy, nitrate,phosphate, diphosphate, succinyloxy, sulfoxy, trifluoromethanesulfoxy,trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy;

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein when X⁻ is absent optionally the counterion is aninternal salt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoicacid (being lactic acid; the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid selectedfrom formic acid, acetic acid, propionic acid, or butyric acid, beingformate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion of ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, substituted carbonate, substitutedglutathione, and substituted glutathione disulfide are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁶ is selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′,—C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl, substituted orunsubstituted (C₁-C₈)cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitaminB6 ester, choline ester, biotin ester, vitamin A ester, resveratrolester, glutathione ester, glutathione disulfide ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (2), or salts thereof, includecompounds or derivatives having formula (2a), or salts thereof:

wherein R⁶ is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, andsubstituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester,resveratrol ester, glutathione ester, glutathione disulfide ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹⁴ is methyl or phenyl;

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with one embodiment, the present disclosure provides anovel method for the preparation of compounds or derivatives havingformula (I-H), or salts, solvates, or prodrugs thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen. In accordance with such an embodiment, thepresent disclosure provides a novel method whereby mechanic forces areused to minimize solvent quantities, decrease reaction times, increaseoverall conversion, and facilitate product purification in a multistepsynthetic sequence, whereby by-product formation is minimized, andwhereby primarily by-products that can be removed readily by filtrationor evaporation are generated. Prototype product analogs of nicotinoylriboside compounds include compounds or derivatives having formula(I-H), or salts, solvates, or prodrugs thereof, wherein R⁶, R⁷, and R⁸are each hydrogen:

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein when X⁻ is absent optionally the counterion is aninternal salt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoicacid (being lactic acid, the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of an unsubstituted monocarboxylic acidselected from formic acid, acetic acid, propionic acid, or butyric acid,being formate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion of ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, and substituted carbonate,substituted glutathione, and substituted glutathione disulfide aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂,—C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (I-H) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (I-H), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R², R³, R⁴, and R⁵ are each independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂,—C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with an alternative embodiment, prototype product analogsof nicotinoyl riboside compounds include compounds or derivatives havingformula (Ia-H), or salts, solvates, or prodrugs thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen:

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein when X⁻ is absent optionally the counterion is aninternal salt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoicacid (being lactic acid, the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of an unsubstituted monocarboxylic acidselected from formic acid, acetic acid, propionic acid, or butyric acid,being formate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion of ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, substituted carbonate, substitutedglutathione, and substituted glutathione disulfide are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (Ia-H) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (Ia-H), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₂—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R², R³, R⁴, and R⁵ are each hydrogen;

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with one embodiment, the present disclosure provides anovel method for the preparation of compounds or derivatives havingformula (II), or salts, solvates, or prodrugs thereof, such asphosphorylated analogs of nicotinoyl ribosides, in commercialquantities. In accordance with such an embodiment, the presentdisclosure provides a novel method whereby mechanic forces are used tominimize solvent quantities, decrease reaction times, increase overallconversion, and facilitate product purification in a multistep syntheticsequence, whereby by-product formation is minimized, and wherebyprimarily by-products that can be removed readily by filtration orevaporation are generated. Prototype product phosphorylated analogs ofnicotinoyl ribosides compounds include compounds or derivatives havingformula (II), or salts, solvates, or prodrugs thereof:

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein when X⁻ is absent optionally the counterion is aninternal salt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoicacid (being lactic acid, the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of an unsubstituted monocarboxylic acidselected from formic acid, acetic acid, propionic acid, or butyric acid,being formate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion of ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, substituted carbonate, substitutedglutathione, and substituted glutathione disulfide are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each Y¹ and Y² is independently selected from the group consisting ofhydrogen, sodium, potassium, lithium, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2),niacin (vitamin B3), pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, substituted heterocycle, andsubstituted amino are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, Y¹ and Y² taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein Y³ is oxygen, sulfur, or absent;

each of Z¹ and Z² is independently NH or oxygen;

each of Z³ and Z⁴ is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

q is 1 or 2;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (II) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (II), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R², R³, R⁴, and R⁵ are each independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C),—C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with an alternative embodiment, the present disclosureprovides a novel method for the preparation of compounds or derivativeshaving formula (IIa), or salts, solvates, or prodrugs thereof, such asphosphorylated analogs of nicotinoyl ribosides, in commercialquantities. In accordance with such an embodiment, the presentdisclosure provides a novel method whereby mechanic forces are used tominimize solvent quantities, decrease reaction times, increase overallconversion, and facilitate product purification in a multistep syntheticsequence, whereby by-product formation is minimized, and wherebyprimarily by-products that can be removed readily by filtration orevaporation are generated. Prototype product phosphorylated analogs ofnicotinoyl riboside compounds include compounds or derivatives havingformula (IIa), or salts, solvates, or prodrugs thereof:

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein when X⁻ is absent optionally the counterion is aninternal salt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoicacid (being lactic acid, the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of an unsubstituted monocarboxylic acidselected from formic acid, acetic acid, propionic acid, or butyric acid,being formate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion of ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, substituted carbonate, substitutedglutathione, and substituted glutathione disulfide are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each Y¹ and Y² is independently selected from the group consisting ofhydrogen, sodium, potassium, lithium, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2),niacin (vitamin B3), pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, substituted heterocycle, andsubstituted amino are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, Y¹ and Y² taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein Y³ is oxygen, sulfur, or absent;

each of Z¹ and Z² is independently NH or oxygen;

each of Z³ and Z⁴ is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

q is 1 or 2;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (IIa) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (IIa), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

each of R², R³, R⁴, and R⁵ is hydrogen;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with one embodiment, the present disclosure provides anovel method for the preparation of compounds or derivatives havingformula (III), or salts, solvates, or prodrugs thereof, in commercialquantities. In accordance with such an embodiment, the presentdisclosure provides a novel method whereby mechanic forces are used tominimize solvent quantities, decrease reaction times, increase overallconversion, and facilitate product purification, whereby by-productformation is minimized. Prototype product nicotinyl riboside compoundsinclude compounds or derivatives having formula (III), or salts,solvates, or prodrugs thereof:

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein X⁻ is absent optionally the counterion is an internalsalt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxylpropanoicacid (being lactic acid, the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of an unsubstituted monocarboxylic acidselected from formic acid, acetic acid, propionic acid, or butyric acid,being formate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion of ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, substituted carbonate, substitutedglutathione, and substituted glutathione disulfide are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each Y¹ is independently selected from the group consisting of hydrogen,sodium, potassium, lithium, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstituted amino,thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3),pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, substituted heterocycle, and substituted aminoare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each W¹ is independently selected from the group consisting of hydrogen,sodium, potassium, lithium, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstituted amino,thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3),pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, substituted heterocycle, and substituted aminoare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, Y¹ and W¹ taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein Y³ is oxygen, sulfur, or absent;

optionally wherein W³ is oxygen, sulfur, or absent;

each of Z¹ and Z² is independently NH or oxygen;

each of Z³ and Z⁵ is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

q is 1 or 2;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (III) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (III), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R², R³, R⁴, and R⁵ are each independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂,—C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹¹ is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹² is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each R¹³ is independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (III), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (3),or salts thereof:

wherein each W¹ and W² is independently selected from the groupconsisting of hydrogen, sodium, potassium, lithium, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin(vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6),—N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and—C**H—(R^(A))—CO₂R^(B); wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, and substituted amino are substituted with oneto five substituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, W¹ and W² taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein W³ is oxygen, sulfur, or absent;

each of Z⁵ and Z⁶ is independently nitrogen or oxygen;

t is 1 or 2;

u is 1 or 2;

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R¹¹ is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹² is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR)NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each R¹³ is independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with an alternative embodiment, the present disclosureprovides a novel method for the preparation of compounds or derivativeshaving formula (IIIa), or salts, solvates, or prodrugs thereof, incommercial quantities. In accordance with such an embodiment, thepresent disclosure provides a novel method whereby mechanic forces areused to minimize solvent quantities, decrease reaction times, increaseoverall conversion, and facilitate product purification, wherebyby-product formation is minimized. Prototype product nicotinoyl ribosidecompounds include compounds or derivatives having formula (IIIa), orsalts, solvates, or prodrugs thereof:

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein when X⁻ is absent optionally the counterion is aninternal salt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoicacid (being lactic acid, the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of an unsubstituted monocarboxylic acidselected from formic acid, acetic acid, propionic acid, or butyric acid,being formate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, substituted carbonate, substitutedglutathione, and substituted glutathione disulfide are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each Y¹ is independently selected from the group consisting of hydrogen,sodium, potassium, lithium, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstituted amino,thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3),pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, substituted heterocycle, and substituted aminoare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each W¹ is independently selected from the group consisting of hydrogen,sodium, potassium, lithium, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstituted amino,thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3),pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, substituted heterocycle, and substituted aminoare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, Y¹ and W¹ taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein Y³ is oxygen, sulfur, or absent;

optionally wherein W³ is oxygen, sulfur, or absent;

each of Z¹ and Z² is independently NH or oxygen;

each of Z³ and Z⁵ is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

q is 1 or 2;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (IIIa) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (IIIa), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

each of R², R³, R⁴, and R⁵ is hydrogen;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹¹ is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹² is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each R¹³ is independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (IIIa), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (3),or salts thereof:

wherein each W¹ and W² is independently selected from the groupconsisting of hydrogen, sodium, potassium, lithium, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin(vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6),—N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and—C**H—(R^(A))—CO₂R^(B); wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, and substituted amino are substituted with oneto five substituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, W¹ and W² taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein W³ is oxygen, sulfur, or absent;

each of Z⁵ and Z⁶ is independently nitrogen or oxygen;

t is 1 or 2;

u is 1 or 2;

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R¹¹ is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹² is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each R¹³ is independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with one embodiment, the present disclosure provides anovel method for the preparation of compounds or derivatives havingformula (IV), or salts, solvates, or prodrugs thereof, such as reducednicotinoyl ribosides and their derivatives, and including, but notlimited to, the triacetylated forms of NRH (reduced nicotinamideriboside) and NARH (reduced nicotinic acid riboside) (compounds orderivatives having formula (IV), wherein R⁶, R⁷, and R⁸ are each acetylgroups), and the fully deprotected forms thereof (compounds orderivatives having formula (IV-H), wherein R⁶, R⁷, and R⁸ are eachhydrogen), in commercial quantities. In accordance with such anembodiment, the present disclosure provides a novel method wherebymechanic forces and/or sealed conditions, and extraction conditions, areused to minimize solvent and reagent quantities, decrease reactiontimes, increase overall conversion, and facilitate product purificationin a multistep synthetic sequence, whereby by-product formation isminimized, and whereby primarily by-products that can be removed readilyby filtration or evaporation are generated. Prototype product reducednicotinoyl riboside compounds include compounds or derivatives havingformula (IV), or salts, solvates, or prodrugs thereof:

wherein Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (IV) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (IV), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R² and R³ are each independently selected from the group consisting ofhydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN,—NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁴ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein C* has an absolute configuration of R or S, or a mixture of Rand S;

R⁵ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁶ is selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′,—C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl, substituted orunsubstituted (C₁-C₈)cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitaminB6 ester, choline ester, biotin ester, vitamin A ester, resveratrolester, glutathione ester, glutathione disulfide ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with an alternative embodiment, prototype product reducednicotinoyl riboside compounds include compounds or derivatives havingformula (IVa), or salts, solvates, or prodrugs thereof:

wherein Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (IVa) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (Iva), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

each of R², R³, R⁴, and R⁵ is hydrogen;

R⁶ is selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′,—C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl, substituted orunsubstituted (C₁-C₈)cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitaminB6 ester, choline ester, biotin ester, vitamin A ester, resveratrolester, glutathione ester, glutathione disulfide ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with one embodiment, the present disclosure provides anovel method for the preparation of compounds or derivatives havingformula (IV-H), or salts, solvates, or prodrugs thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen. In accordance with such an embodiment, thepresent disclosure provides a novel method whereby mechanic forces areused to minimize solvent and reagent quantities, decrease reactiontimes, increase overall conversion, and facilitate product purificationin a multistep or single-step synthetic sequence, whereby by-productformation is minimized, and whereby by-products that are removed readilyby filtration or evaporation are generated. Prototype product reducednicotinoyl riboside compounds include compounds or derivatives havingformula (IV-H), or salts, solvates, or prodrugs thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen:

wherein Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (IV-H) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (IV-H), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R² and R³ are each independently selected from the group consisting ofhydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN,—NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁴ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein C* has an absolute configuration of R or S, or a mixture of Rand S;

R⁵ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with an alternative embodiment, prototype product reducednicotinoyl riboside compounds include compounds or derivatives havingformula (IVa-H), or salts, solvates, or prodrugs thereof, wherein R⁶,R⁷, and R⁸ are each hydrogen:

wherein Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (IVa-H) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (IVa-H), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

each of R², R³, R⁴, and R⁵ is hydrogen;

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with one embodiment, the present disclosure provides anovel method for the preparation of compounds or derivatives havingformula (V), or salts, solvates, or prodrugs thereof, such asphosphorylated analogs of reduced nicotinoyl ribosides, in commercialquantities. In accordance with such an embodiment, the presentdisclosure provides a novel method whereby mechanic forces are used tominimize solvent quantities, decrease reaction times, increase overallconversion, and facilitate product purification in a multistep syntheticsequence, whereby by-product formation is minimized, and wherebyprimarily by-products that can be removed readily by filtration orevaporation are generated. Prototype product phosphorylated analogs ofreduced nicotinoyl riboside compounds include compounds or derivativeshaving formula (V), or salts, solvates, or prodrugs thereof:

wherein each Y¹ and Y² is independently selected from the groupconsisting of hydrogen, sodium, potassium, lithium, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin(vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6),—N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and—C**H—(R^(A))—CO₂R^(B); wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, and substituted amino are substituted with oneto five substituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, Y¹ and Y² taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein Y³ is oxygen, sulfur, or absent;

each of Z¹ and Z² is independently NH or oxygen;

each of Z³ and Z⁴ is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

q is 1 or 2;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (V) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (V), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R² and R³ are each independently selected from the group consisting ofhydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN,—NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁴ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein C* has an absolute configuration of R or S, or a mixture of Rand S;

R⁵ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (V), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (IVb),or salts, solvates, or prodrugs thereof:

Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (IVb) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (IVb), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R² and R³ are each independently selected from the group consisting ofhydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN,—NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁴ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein C* has an absolute configuration of R or S, or a mixture of Rand S;

R⁵ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with an alternative embodiment, the present disclosureprovides a novel method for the preparation of compounds or derivativeshaving formula (Va), or salts, solvates, or prodrugs thereof, such asphosphorylated analogs of reduced nicotinoyl ribosides, in commercialquantities. In accordance with such an embodiment, the presentdisclosure provides a novel method whereby mechanic forces are used tominimize solvent quantities, decrease reaction times, increase overallconversion, and facilitate product purification in a multistep syntheticsequence, whereby by-product formulation is minimized, and wherebyprimarily by-products that can be removed readily by filtration orevaporation are generated. Prototype product phosphorylated analogs ofreduced nicotinoyl riboside compounds include compounds or derivativeshaving formula (Va), or salts, solvates, or prodrugs thereof:

wherein each Y¹ and Y² is independently selected from the groupconsisting of hydrogen, sodium, potassium, lithium, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin(vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6),—N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and—C**H—(R^(A))—CO₂R^(B); wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, and substituted amino are substituted with oneto five substituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, Y¹ and Y² taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein Y³ is oxygen, sulfur, or absent;

each of Z¹ and Z² is independently NH or oxygen;

each of Z³ and Z⁴ is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

q is 1 or 2;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (Va) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (Va), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

each of R², R³, R⁴, and R⁵ is hydrogen;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (Va), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (IVc),or salts, solvates, or prodrugs thereof:

Z¹ and Z² are independently NH or oxygen;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (IVc) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (IVc), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

each of R², R³, R⁴, and R⁵ is hydrogen;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with one embodiment, the present disclosure provides anovel method for the preparation of compounds or derivatives havingformula (VI), or salts, solvates, or prodrugs thereof, such as adenylyldinucleotide conjugates of reduced nicotinoyl ribosides, in commercialquantities. In accordance with such an embodiment, the presentdisclosure provides a novel method whereby mechanic forces are used tominimize solvent quantities, decrease reaction times, increase overallconversion, and facilitate product purification, whereby by-productformation is minimized. Prototype product reduced nicotinoyl ribosidecompounds include compounds or derivatives having formula (VI), orsalts, solvates, or prodrugs thereof:

wherein each Y¹ is independently selected from the group consisting ofhydrogen, sodium, potassium, lithium, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2),niacin (vitamin B3), pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, substituted heterocycle, andsubstituted amino are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each W¹ is independently selected from the group consisting of hydrogen,sodium, potassium, lithium, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstituted amino,thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3),pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, substituted heterocycle, and substituted aminoare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, Y¹ and W¹ taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein Y³ is oxygen, sulfur, or absent;

optionally wherein W³ is oxygen, sulfur, or absent;

each of Z¹ and Z² is independently NH or oxygen;

each of Z³ and Z⁵ is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

q is 1 or 2;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (VI) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (VI), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R² and R³ are each independently selected from the group consisting ofhydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN,—NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁴ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein C* has an absolute configuration of R or S, or a mixture of Rand S;

R⁵ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹¹ is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹² is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each R¹³ is independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the methods of the present disclosure for the preparation ofcompounds or derivatives having formula (VI), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (3),or salts thereof:

wherein each W¹ and W² is independently selected from the groupconsisting of hydrogen, sodium, potassium, lithium, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin(vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6),—N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and—C**H—(R^(A))—CO₂R^(B); wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, and substituted amino are substituted with oneto five substituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, W¹ and W² taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein W³ is oxygen, sulfur, or absent;

each of Z⁵ and Z⁶ is independently nitrogen or oxygen;

t is 1 or 2;

u is 1 or 2;

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R¹¹ is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹² is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each R¹³ is independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with an alternative embodiment, the present disclosureprovides a novel method for the preparation of compounds or derivativeshaving formula (VIa), or salts, solvates, or prodrugs thereof, such asadenylyl dinucleotide conjugates of reduced nicotinoyl ribosides, incommercial quantities. In accordance with such an embodiment, thepresent disclosure provides a novel method whereby mechanic forces areused to minimize solvent quantities, decrease reaction times, increaseoverall conversion, and facilitate product purification, wherebyby-product formation is minimized. Prototype product nicotinoyl ribosidecompounds include compounds or derivatives having formula (VIa), orsalts, solvates, or prodrugs thereof:

wherein each Y¹ is independently selected from the group consisting ofhydrogen, sodium, potassium, lithium, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2),niacin (vitamin B3), pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, substituted heterocycle, andsubstituted amino are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each W¹ is independently selected from the group consisting of hydrogen,sodium, potassium, lithium, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstituted amino,thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3),pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, substituted heterocycle, and substituted aminoare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, Y¹ and W¹ taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein Y³ is oxygen, sulfur, or absent;

optionally wherein W³ is oxygen, sulfur, or absent;

each of Z¹ and Z² is independently NH or oxygen;

each of Z³ and Z⁵ is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

q is 1 or 2;

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, pterostilbene ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, and n is 0, the compound orderivative having formula (VIa) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (VIa), further optionally associated with a positivelycharged counterion selected from the group consisting of alkali metal,alkaline earth metal, transition metal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

each of R², R³, R⁴, and R⁵ is hydrogen;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹¹ is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹² is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each R¹³ is independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

In accordance with such an embodiment, appropriate starting materialsfor the method of the present disclosure for the preparation ofcompounds or derivatives having formula (VIa), or salts, solvates, orprodrugs thereof, include compounds or derivatives having formula (3),or salts thereof:

wherein each W¹ and W² is independently selected from the groupconsisting of hydrogen, sodium, potassium, lithium, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin(vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6),—N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and—C**H—(R^(A))—CO₂R^(B); wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, and substituted amino are substituted with oneto five substituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, W¹ and W² taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein W³ is oxygen, sulfur, or absent;

Z⁵ and Z⁶ are independently nitrogen or oxygen;

t is 1 or 2;

u is 1 or 2;

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R¹¹ is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substitutentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹² is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, —(C₁-C₆)alkylene-OR^(C);

each R¹³ is independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

Definitions

As used in the specification and the appended claims, the singular formsof“a,” “an,” and “the” include plural referents unless the contextclearly dictates otherwise.

As used herein, the term “Lewis acid” refers to any chemical speciesthat can accept a pair of nonbonding valence electrons, i.e., anelectron-pair acceptor. Without limitation, non-limiting examples ofLewis acids include BF₃, TMSOTf, and SnCl₄.

As used herein, the term “solvent” refers to a compound or mixture ofcompounds including, but not limited to, water, water in which an ioniccompound has been dissolved, acetic acid, acetone, acetonitrile,benzene, 1-butanol, 2-butanol, t-butyl alcohol (“TBA”), 2-butanone,carbon tetrachloride, chlorobenzene, chloroform, cyclohexane,1,2-dichloroethane (“DCE”), diethylene glycol, diethyl ether (“Et₂O”),diglyme (diethylene glycol dimethyl ether), 1,2-dimethoxyethane (“DME”),N,N-dimethylformamide (“DMF”), dimethylsulfoxide (“DMSO”), 1,4-dioxane,ethanol, ethyl acetate (“EtOAc”), ethylene glycol, glycerin, heptanes,hexamethylphosphoramide (“HMPA”), hexamethylphosphorus triamide(“HMPT”), hexane, methanol (“MeOH”), methyl t-butyl ether (“MTBE”),methylene chloride (“DCM,” “CH₂Cl₂”), N-methyl-2-pyrrolidinone (“NMP”),nitromethane, pentane, petroleum ether, 1-propanol (“n-propanol,”“n-PrOH”), 2-propanol (“isopropanol,” “iPrOH”), pyridine,tetrahydrofuran (“THF”), toluene, triethylamine (“TEA,” “Et₃N”),o-xylene, m-xylene, and/or p-xylene, and the like. Solvent classes mayinclude hydrocarbon, aromatic, aprotic, polar, alcoholic, and mixturesthereof.

As used herein, the terms “mechano-chemical mixing,” “mechanochemistry,”and “mechanical processing” refer to standard techniques known to thoseof ordinary skill in the art, in which chemical starting materialsand/or reagents with disparate solubility properties are reacted, forexample, by direct milling, liquid assisted-milling, triturating,mixing, or grinding, generally in the absence of solvents.Interchangeable terms may include “mechanic-chemical,” or the like. SeeF. Ravalico et al., Rapid synthesis of nucleotide pyrophosphate linkagesin a ball mill, 9 ORG. BIOL. CHEM. 6496 (2011); Dritan Hasa et al.,Cocrystal Formation through Mechanochemistry: From Neat andLiquid-Assisted Grinding to Polymer-Assisted Grinding, 127 ANGEWANDTECHEMIE 7371 (2015); and references cited therein, all of which areincorporated by reference herein in their entireties.

As used herein, the term “liquid-assisted mixing” refers to a standardtechnique known to those of ordinary skill in the art, in which thekinetics of solid-state grinding is accelerated by addition of a smallamount of liquid during mixing. It was discovered in 2001 that not onlydid small amounts of liquid speed up the solid-state reaction, but innumerous cases, addition of small amounts of liquid allowed theformation of new solid forms that could not otherwise be made. See N.Shan et al., Mechanochemistry and co-crystal formation: effect ofsolvent on reaction kinetics, CHEM. COMMC'NS 2732 (2002), incorporatedby reference herein in its entirety. Between 2002 and 2005 it wasdiscovered that the exact outcome of the solid-state grinding could becontrolled by careful choice of the added liquid. See A. V. Trask etal., Achieving Polymorphic and Stoichiometric Diversity in CocrystalFormation: Importance of Solid-State Grinding, Powder X-ray StructureDifferentiation, and Seeding, 5 CRYSTAL GROWTH & DESIGN 2233 (2005),incorporated by reference herein in its entirety. Between 2005 and 2007,it was further demonstrated that this liquid-assisted mixing approach issignificantly more effective in searching for alternate solid forms ofdrug candidates than other previously used methods, e.g., conventionalsolution crystallization or melt growth. See S. Karki et al., Screeningfor pharmaceutical cocrystal hydrates via neat and liquid-assistedgrinding, 4 MOLECULAR PHARMACEUTICS 347 (2007); A. V. Trask et al.,Screening for crystalline salts via mechanochemistry, CHEM. COMMC'NS 51(2006); each of which is incorporated by reference herein in itsentirety. Liquid-assisted mixing is a method that is rapid andenvironmentally friendly because it eliminates the need to use largeamounts of solvents, cutting down on waste and lost revenue.

As used therein, the term “extrusion” refers to a standard techniqueknown to those of ordinary skill in the art, in which a raw material ischemically converted into a product of unique shape and density byforcing it through a die under defined conditions. See J. Thiry et al.,A review of pharmaceutical extrusion: Critical process parameters andscaling-up, 479 INT'L J. PHARMACEUTICS 227 (2015), incorporated byreference herein in its entirety. An extruder is composed of twodifferent parts: a conveying system and a die system. The conveyingsystem transports the material through the barrel via the action ofArchimedes' infinite screws, which can also impart a degree ofdistributive mixing if needed. The die system then forms the materialinto the desired shape. See id. Pharmaceutical extrudates are generallyproduced by heating and then softening a mixture of a drug and athermoplastic polymer, followed by extrusion of the molten mass througha die, resulting in the production of cylinders of films depending onthe shape of the die. In addition, other excipients, such assurfactants, salts, superdisintegrants, plasticizers, and antioxidantsmay be added during the extrusion process if required. See K. Hughey etal., The use of inorganic salts to improve the dissolutioncharacteristics of tablets containing Soluplus®-based solid dispersions,48 EUR. J. PHARM. SCI. 758 (2013); M. A. Repka et al., Pharmaceuticalapplications of hot-melt extrusion: part II, 33 DRUG DEV. INDUS. PHARM.1043 (2007), each of which is incorporated by reference herein in itsentirety. The most common additives are plasticizers, which facilitatethe extrusion process by reducing the glass transition temperature ofthe polymers. See M. M. Crowley et al., Pharmaceutical applications ofhot-melt extrusion: part I, 33 DRUG DEV. INDUS. PHARM. 909 (2007),incorporated by reference herein in its entirety. The release of theactive pharmaceutical ingredient (“API”) and the quality of the finalproduct can be fine-tuned by modifying the excipients. For example, somepolymers have a different dissolution pH, which can allow the targetingof a specific part of the gastro-intestinal tract. See D. A. Miller etal., Targeted intestinal delivery of supersaturated itraconazole forimproved oral absorption, 25 PHARM. RES. 1450 (2008), incorporated byreference herein in its entirety. Some polymers can also control therelease of the API in order to observe an immediate, delayed, orsustained release. See S. Janssens et al., The use of a new hydrophilicpolymer, Kollicoat IR®, in the formulation of solid dispersions ofitraconazole, 30 EUR. J. PHARM. SCI. 288 (2007); L. D. Bruce et al.,Properties of hot-melt extruded tablet formulations for the colonicdelivery of 5-aminosalicylic acid, 59 EUR. J. PHARM. BIOPHARM. 85(2005); E. Verhoeven et al., Xanthan gum to tailor drug release ofsustained-release ethylcellulose mini-matrices prepared via hot-meltextrusion: in vitro and in vivo evaluation, 63 EUR. J. PHARM. BIOPHARM.320 (2006); each of which is incorporated by reference herein in itsentirety. Another very important aspect to bear in mind is the affinitybetween the API and the polymer matrix, especially when aiming forenhancement of the bioavailability of poorly soluble drugs. See Shah etal., Melt extrusion with poorly soluble drugs, 453 INT'L J. PHARM. 233(2013), incorporated by reference herein in its entirety. It is for thisreason that a screening process of different polymers is generallyneeded in order to obtain the best solid dispersion. See Sarode et al.,Hot melt extrusion (HME) for amorphous solid dispersions: predictivetools for processing and impact of drug-polymer interactions onsupersaturation, 48 EUR. J. PHARM. SCI. 371 (2002), incorporated byreference here in its entirety. The formulation step is therefore veryimportant, because it will have a critical impact on the final qualityof the product.

Because extrusion is a complex process, which is very versatile andflexible, the process parameters need to be taken into account in orderto obtain the best final product. See Romanski et al., The importance ofmonitoring process parameters as a method for quality control for hotmelt extrusion, AAPS ANNUAL MEETING, SAN ANTONIO, TX (2013),incorporated by reference herein in its entirety. A typical extrusionsetup consists of: a motor, which acts as a drive unit; an extrusionbarrel; a rotating screw; and an extrusion die. See R. Chokshi & H. Zia,Hot-melt extrusion technique: a review, 3 IRAN J. PHARM. RES. 3 (2004),incorporated by reference herein in its entirety. The extruder must beable to rotate the screw at a predetermined speed. At the same time, thetorque and shear generated by the extruded material, and the screws mustbe compensated. The extruder is connected to a central control unit inorder to control the process parameters, such as screw speed andtemperature, and therefore pressure. This electronic control unit willalso act as a monitoring system. See M. Maniruzzaman et al., A review ofhot-melt extrusion: process technology to pharmaceutical products, ISRNPHARM. (2012), incorporated by reference herein in its entirety. A veryimportant characteristic to consider, regardless of whether theextrusion equipment is a single screw (“ssEr”) or twin screw extruder(“tsEr”), is the length to diameter ratio (L/D) of the screws. The L/Dtypically ranges from about 20 to about 40:1 (mm). Another importantcharacteristic is the diameter of the screws, because this willdetermine the size of the equipment and its throughput. The screwdiameters of pilot extruders range from about 12 to about 30 mm, whilethe production machines for pharmaceutical scaling-up are much larger,with diameters typically exceeding about 50 to about 60 mm. See G.Andrews et al., A Basic Guide: Hot-Melt Extrusion, 13 UKICRS (2008),incorporated by reference herein in its entirety. Process analyticaltechnology such as near infrared (“NIR”) and Raman, can also be appliedto the extruder setup via probes in order to control in-line the qualityof the final product. See F. Krier et al., PAT tools for the control ofco-extrusion implants manufacturing process, 458 INT'L J. PHARM. 15(2013), incorporated by reference herein in its entirety. Throughout thewhole process, the temperature of the different sections is controlledby electrical heating bands around the barrel or by heating cartridgesinside the barrel, and is monitored by thermocouples.

Temperature is the first factor to take into account in the extrusionprocess, because the polymer has to be processed above its glasstransition temperature (T_(g)), but below its degradation temperature(T_(deg)). The API can be processed below or above its meltingtemperature (T_(m)) depending on whether a miscibility regime or asolubilization regime, respectively, is being used. See M. A. Repka etal., Melt extrusion, AAPS (2013), incorporated by reference herein inits entirety. It is well known that the temperature influences theviscosity of the melt. See J. Breitenbach, Melt extrusion from processto drug delivery technology, 54 EUR. J. PHARM. BIOPHARM. 107 (2002),incorporated by reference herein in its entirety. Therefore, anequilibrium has to be found between, on the one hand, a low temperaturewhere the melt shows high viscosity, and thus a high torque, and on theother hand, an elevated temperature where the torque is reduced due tothe low viscosity of the melt but where both the polymer and the APIcould be degraded. The product temperature can consequently be a majordeterminant factor in the quality of the final product. It is importantto note that the product temperature will be different from the barreltemperature. Indeed, mechanical energy is often transferred from thescrews into the molten material.

It is well known that modification of the screw configuration allows formodification of the production method, as the different screw elementscan be optimized to suit particular applications. See Breitenbach(2002); Chokshi & Zia (2004). Moreover, the residence time of the mix inthe barrel will also be influenced by the type of element used duringthe process. For example, adding kneading elements will increase theresidence time. See H. Liu et al., Effects of screw configuration onindomethacin dissolution behavior in eudragit E PO, 31 ADV. POLYM. TECH.331 (2012); P. R. Wahl et al., Inline monitoring and a PAT strategy forpharmaceutical hot melt extrusion, 455 INT'L J. PHARM. 159 (2013); eachof which is incorporated by reference herein in its entirety. Screwconfiguration is a very important parameter in the amorphization of theAPI using twin screw hot melt extrusion (“tsHME”). In their study,Nakamichi et al. concluded that at least one mixing zone was needed inorder to obtain smooth and homogeneous extrudates while processingnifedipine and hydroxypropylmethylcellulose phthalate with the kneedingpaddle positioned at the level of the second third of the barrel. K.Nakamichi et al., The role of the kneading paddle and the effects ofscrew revolution speed and water content on the preparation of SD usingtwin-screw extruder, 241 INT'L J. PHARM. 203 (2002), incorporated byreference herein in its entirety. The samples were recovered from thescrew directly and analyzed by DSC and x-ray diffraction (“XRD”).Moreover, when studying the release of the drug in vitro,supersaturation was only observed when the kneading paddle was present.Verhoeven et al. observed the same result while extruding ethylcellulosewith metoprolol tartrate (“MPT”). Further, these authors changed thenumber of mixing zones and their position within the barrel, but mixingefficacy and drug release were found not to be effected by thosechanges. See E. Verhoeven et al., Influence of formulation and processparameters on the release characteristics of ethylcellulosesustained-release mini-matrices produced by hot-melt extrusion, 69 EUR.J. PHARM. BIOPHARM. 312 (2008), incorporated by reference herein in itsentirety.

The screw speed also needs to be adapted for each purpose, because ithas an impact on several factors involved in the extrusion process. Onthe one hand, if amorphization is targeted, the screw speed would needto be high in order to obtain a high shear mixing with reduced residencetime. On the other hand, in order to obtain high purity cocrystals, thescrew speed would need to be reduced so as to increase the residencetime, and consequently, the mixing time.

Regarding feeding material into the extruder, first of all, varying thefeed rate, while maintaining the screw speed as constant, will changethe fill level of the extrusion barrel, because increasing the feed ratewill increase the filling rate. See E. Reitz et al., Residence timemodeling of hot melt extrusion processes, 85 EUR. J. PHARM. BIOPHARM.1200 (2013), incorporated by reference herein in its entirety. Almeidaet al. concluded that a balance needs to be found between feed rate andscrew speed in order to maintain a constant melt flow. See A. Almeida etal., Upscaling and inline process monitoring via spectroscopictechniques of ethylene vinyl acetate hot-melt extruded formulations, 439INT'L J. PHARM. 223 (2012), incorporated by reference herein in itsentirety. Generally, the filling percentage of the extruder barrel iscomprised between about 20% and about 50%, and this can be calculated byusing the following equation:

${{Filling}\mspace{14mu}\%} = {\frac{{FR} \times {RTD}}{\rho \times V_{free}} \times 100}$where “FR” is the feed rate (g/min), “RTD” is the mean residence time(min), “ρ” is the bulk viscosity of the polymer/mix (g/mL), and“V_(free)” is the extruder free volume (mL). See A. Swanborough, Apractical approach to scale-up from bench-top. Twin Screw Extruders,THERMO FISHER SCIENTIFIC INC. (2006), incorporated by reference hereinin its entirety.

Before scaling up the extrusion process, it is recommended to measurethe specific mechanical energy (“SME”) on a laboratory scale extruder toallow the prediction of the performance of a production extruder,operating under similar conditions of screw speed and residence time.See Swanborough, 2006. Therefore, all of the parameters described aboveneed to be adapted in order to obtain the same results. When scaling upthe extrusion process, larger screws, higher screw speeds, and higherfeeding rates will be used. However, two factors—the SME and theresidence time—must be maintained at a similar level, even if the scaleof the process is increased. Therefore, the critical parameters of theprocess must be adapted in order to fit these two factors.

In accordance with one embodiment, methods for preparation of thepresent disclosure comprise processing by extruding, wherein theextruder is a 11-millimeter, stainless steel, twin screw jacketedextruder, and wherein the processing by extruding includesinterchangeable mixing elements, independent heating and cooling zones,programmable feeding, and liquid injection ports.

Without limitation, non-limiting examples of Brønsted acids include HI,HCl, HBr, H₂SO₄, H₃O⁺, HNO₃, H₃PO₄, and CH₃CO₂H. Without limitation,non-limiting examples of Brønsted bases include CH₃ ⁻, CH₂═CH⁻, H⁻, NH₂⁻, HC≡C⁻, CH₃O⁻, HO⁻, HS⁻, CO₃ ⁻², NH₃, HCO₂ ⁻, MeO⁻, and EtO⁻.

Without limitation, and without being bound by theory, as used herein,the terms “oxidizing agent,” “oxidant,” and “electron acceptor” refer tospecies that gain electrons and are reduced in a chemical reaction. Anoxidizing agent is normally in one of its higher possible oxidationstates because it will gain electrons and be reduced. Withoutlimitation, non-limiting examples of oxidizing agents include, but arenot limited to, O₂, O₃, H₂SO₄, and the halogen elements.

Without limitation, and without being bound by theory, as used herein,the terms “reducing agent,” “reductant,” and “electron donor” refer tospecies that lose electrons and are oxidized in a chemical reaction. Areducing agent is typically in one of its lower possible oxidationstates because it will lose electrons and be oxidized. Withoutlimitation, non-limiting examples of reducing agents include, but arenot limited to, H₂, CO, Fe, Zn, and the alkali metal elements.

Without limitation, and without being bound by theory, as used herein,the term “catalysis” or “catalytic” refers an increase in the rate of achemical reaction of a substrate species due to the participation of anadditional chemical species called a “catalyst,” which is not consumedin the catalyzed reaction and can continue to act repeatedly insubsequent repetitions of the same chemical reaction. In particularembodiments, by “catalytic amount” is meant that a chemical species ispresent in no greater an amount than 10% molar equivalent amountrelative to the amount of substrate. In other embodiments, by “catalyticamount” is meant that a chemical species is present in no greater anamount than 5% molar equivalent amount relative to the amount ofsubstrate. In yet other embodiments, by “catalytic amount” is meant thata chemical species is present in no greater an amount than 3% molarequivalent amount relative to the amount of substrate. In yet otherembodiments, by “catalytic amount” is meant that a chemical species ispresent in no greater an amount than 1% molar equivalent amount relativeto the amount of substrate.

According to particular embodiments, the compounds or derivativesprepared according to embodiments of the methods of the presentdisclosure can comprise compounds or derivatives, or salts, solvates, orprodrugs thereof, or crystalline forms thereof, substantially free ofsolvents or other by-products, generally, or a particular solvent orby-product. In certain embodiments, by “substantially free” is meantgreater than about 80% free of solvents or by-products, or greater thanabout 80% free of a particular solvent or by-product, more preferablygreater than about 90% free of solvents or by-products, or greater thanabout 90% free of a particular solvent or by-product, even morepreferably greater than about 95% free of solvents or by-products, orgreater than about 95% free of a particular solvent or by-product, evenmore preferably greater than about 98% free of solvents or by-products,or greater than about 98% free of a particular solvent or by-product,even more preferably greater than about 99% free of solvents orby-products, or greater than about 99% free of a particular solvent orby-product, even more preferably greater than about 99.99% free ofsolvents or by-products, or greater than about 99.99% free of aparticular solvent or by-products, and most preferably quantitativelyfree of solvents or by-products, or quantitatively free of a particularsolvent or by-product.

According to particular embodiments, the compounds or derivativesprepared according to embodiments of the methods of the presentdisclosure can comprise compounds or derivatives, or salts, solvates, orprodrugs thereof, or crystalline forms thereof, substantially free ofsolvents or other by-products, generally, or a particular solvent orby-product. In certain embodiments, by “substantially free” is meantless than about 10,000 ppm of solvents or by-products, or less thanabout 10,000 ppm of a particular solvent or by-product, even morepreferably less than about 1,000 ppm of solvents or by-products, or lessthan about 1,000 ppm of a particular solvent or by-product, even morepreferably less than about 100 ppm of solvents or by-products, or lessthan about 100 ppm of a particular solvent or by-product, even morepreferably less than about 10 ppm of solvents or by-products, or lessthan about 10 ppm of a particular solvent or by-product, even morepreferably less than 5 ppm of solvents or by-products, or less than 5ppm of a particular solvent or by-product, and most preferably, anundetectable amount of solvents or by-products, or an undetectableamount of a particular solvent or by-product.

The term “alkyl,” by itself or as part of another substituent means,unless otherwise stated, a straight, branched, or cyclic chainhydrocarbon (“cycloalkyl”) having the number of carbon atoms designated(i.e., C₁-C₆ means one to six carbons). Examples include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl,hexyl, cyclohexyl, and cyclopropyl. Most preferred are —(C₁-C₃)alkyl,particularly ethyl, methyl, and isopropyl.

The term “alkenyl,” employed alone or in combination with other terms,means unless otherwise stated, a stable mono-unsaturated ordi-unsaturated straight chain, the unsaturation meaning a carbon-carbondouble bond (—CH═CH—), branched chain, or cyclic hydrocarbon grouphaving the stated number of carbon atoms. Examples include vinyl,propenyl, allyl, crotyl, isopentenyl, butadienyl, 1,3-pentadienyl,1,4-pentadienyl, cyclopentenyl, cyclopentadienyl, and the higherhomologs and isomers. Functional groups representing an alkene areexemplified by —CH═CH—CH₂— and CH₂═CH—CH₂—.

“Substituted alkyl” or “substituted alkenyl” mean alkyl or alkenyl,respectively, as defined above, substituted by one, two, or threesubstituents. The substituents may, for example, be selected from thegroup consisting of halogen, —OH, —NH₂, —N(CH₃)₂, —C(═O)OH,—C(═O)O(C₁-C₄)alkyl, methoxy, ethoxy, trifluoromethyl, —C(═O)NH₂,—SO₂NH₂, —C(═NH)NH₂, —C≡N, and —NO₂, preferably selected from halogenand —OH. Examples of substituted alkyls include, but are not limited to,2,2-difluoromethyl, 2-carboxycyclopentyl, and 3-chloropropyl.

The term “alkynyl,” employed alone or in combination with other terms,means, unless otherwise stated, a stable carbon-carbon triplebond-containing radical (—C≡C—), branched chain, or cyclic hydrocarbongroup having the stated number of carbon atoms. Examples include ethynyland propargyl.

The term “alkoxy,” employed alone or in combination with other terms,means, unless otherwise stated, an alkyl group having the designatednumber of carbon atoms, as defined above, connected to the rest of themolecule via an oxygen atom, such as, for example, methoxy, ethoxy,1-propoxy, 2-propoxy (“isopropoxy”), and the higher homologs andisomers. Preferred are —(C₁-C₃)alkoxy, particularly ethoxy and methoxy.

The terms “carbamyl” or “carbamoyl” mean the group —C(═O)NRR′, wherein Rand R′ are independently selected from hydrogen or a hydrocarbylfunctional group, or wherein R and R′ combined form a heterocycle.Examples of carbamyl groups include: —C(═O)NH₂ and —C(═O)N(CH₃)₂.

The term “cyano” refers to a —C≡N group.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chainalkyl group consisting of the stated number of carbon atoms and one ortwo heteroatoms selected from the group consisting of O, N, and S, andwherein the nitrogen and sulfur heteroatoms may be optionally oxidizedand the nitrogen heteroatom may be optionally quaternized. Theheteroatom(s) may be placed at any position of the heteroalkyl group,including between the rest of the heteroalkyl group and the fragment towhich it is attached, as well as attached to the most distal carbon atomin the heteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃,—CH₂—CH₂—CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and—CH₂—CH₂—S(═O)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃, or —CH₂—CH₂—S—S—CH₃.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a monovalent fluorine,chlorine, bromine, or iodine atom.

The term “nitro” refers to a —NO₂ group.

The term “(C_(x)-C_(y))perfluoroalkyl,” wherein x<y, means an alkylgroup with a minimum of x carbons and a maximum of y carbons, whereinall hydrogen atoms are replaced by fluorine atoms. Preferred is—(C₁-C₆)perfluoroalkyl, more preferred is —(C₁-C₃)perfluoroalkyl, mostpreferred is —CF₃.

The term “aromatic” generally refers to a carbocycle or heterocyclehaving one or more polyunsaturated rings having aromatic character(i.e., having (4n+2) delocalized π (pi) electrons where n is aninteger).

The term “aryl,” employed alone or in combination with other terms,means, unless otherwise stated, a carbocyclic aromatic system containingone or more rings (typically one, two, or three rings) wherein suchrings may be attached together in a pendant manner, such as a biphenyl,or may be fused, such as naphthalene. Examples include phenyl;anthracyl; and naphthyl. Preferred are phenyl and naphthyl, mostpreferred is phenyl.

The term “2-(methylenyl)phenyl,” employed alone or in combination withother terms, means, unless otherwise stated, a substituted phenyldiradical having the following structural formula:

The terms “heterocycle” or “heterocyclyl” or “heterocyclic,” bythemselves or as part of another substituent, mean, unless otherwisestated, an unsubstituted or substituted, stable, mono- or multi-cyclicheterocyclic ring system that consists of carbon atoms and at least oneheteroatom independently selected from the group consisting of N, O, andS, and wherein the nitrogen and sulfur heteroatoms may be optionallyoxidized, and the nitrogen atom may be optionally quaternized. Theheterocyclic system may be attached, unless otherwise stated, at anyheteroatom or carbon atom that affords a stable structure.

The terms “heteroaryl” or “heteroaromatic” refer to a heterocyclichaving aromatic character. Similarly, the term “heteroaryl(C₁-C₃)alkyl”means a functional group wherein a one to three carbon alkylene chain isattached to a heteroaryl group, e.g., —CH₂—CH₂-pyridyl. The term“substituted heteroaryl(C₁-C₃)alkyl” means a heteroaryl(C₁-C₃)alkylfunctional group in which the heteroaryl group is substituted. Apolycyclic heteroaryl may include fused rings. Examples include indole,1H-indazole, 1H-pyrrolo[2,3-b]pyridine, and the like. A polycyclicheteroaryl may include one or more rings that are partially saturated.Examples include indoline, tetrahydroquinoline, and2,3-dihydrobenzofuryl.

The term “heterocycle(C₁-C₃)alkyl,” by itself or as part of anothersubstituent, means, unless otherwise stated, a functional group whereina (C₁-C₃)alkylene chain is attached to a heterocyclic group, e.g.,morpholino-CH₂—CH₂—. As used herein, the term “substitutedheterocycle(C₁-C₃)alkyl” means a heterocycle(C₁-C₃)alkyl functionalgroup in which the heterocycle group is substituted.

Examples of non-aromatic heterocycles include monocyclic groups such as:aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,4-dihydropyridine, 1,2,3,6-tetrahydropyridine, piperazine,N-methylpiperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran,tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine,homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, andhexamethyleneoxide.

Examples of heteroaryl groups include: pyridyl; pyrazinyl; pyrimidinyl,particularly 2- and 4-pyrimidinyl; pyridazinyl; thienyl; furyl;pyrrolyl, particularly 2-pyrrolyl; imidazolyl; thiazolyl; oxazolyl;pyrazolyl, particularly 3- and 5-pyrazolyl; isothiazolyl;1,2,3-triazolyl; 1,2,4-triazolyl; 1,3,4-triazolyl; tetrazolyl;1,2,3-thiadiazolyl; 1,2,3-oxadiazolyl; 1,3,4-thiadiazolyl; and1,3,4-oxadiazolyl.

Polycyclic heterocycles include both aromatic and non-aromaticpolycyclic heterocycles. Examples of polycyclic heterocycles include:indolyl, particularly 3-, 4-, 5-, 6-, and 7-indolyl; indolinyl;indazolyl, particularly 1H-indazol-5-yl; quinolyl; tetrahydroquinolyl;isoquinolyl, particularly 1- and 5-isoquinolyl;1,2,3,4-tetrahydroisoquinolyl; cinnolyl; quinoxalinyl, particularly 2-and 5-quinoxalinyl; quinazolinyl; phthalazinyl; naphthyridinyl,particularly 1,5- and 1,8-naphthyridinyl; 1,4-benzodioxanyl; coumaryl;dihydrocoumaryl; benzofuryl, particularly 3-, 4-, 5-, 6-, and7-benzofuryl; 2,3-dihydrobenzofuryl; 1,2-benzisoxazolyl; benzothienyl,particularly 3-, 4-, 5-, 6-, and 7-benzoethienyl; benzoxazolyl;benzothiazolyl, particularly 2- and 5-benzothiazolyl; purinyl;benzimidazolyl, particularly 2-benzimidazolyl; benztriazolyl;thioxanthinyl; carbazolyl; carbolinyl; acridinyl; pyrrolizidinyl;pyrrolo[2,3-b]pyridinyl, particularly 1H-pyrrolo[2,3-b]pyridine-5-yl;and quinolizidinyl. Particularly preferred are 4-indolyl, 5-indolyl,6-indolyl, 1H-indazol-5-yl, and 1H-pyrrolo[2,3-b]pyridine-5-yl.

The aforementioned listing of heterocyclic and heteroaryl moieties isintended to be representative and not limiting.

The term “substituted” means that an atom or group of atoms has replacedhydrogen as the substituent attached to another group. For aryl andheteroaryl groups, the term “substituted” refers to any levels ofsubstitution, namely mono-, di-, tri-, tetra-, or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.

D-Ribose stereochemistry has been indicated in compounds or derivativeshaving formulae (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), and(VI), or salts, solvates, or prodrugs thereof. It is understood that theconfiguration at the anomeric carbon can be reversed (i.e., L-), or canbe a mixture of D- and L-.

Synthetic Preparation of Compounds or Derivatives Having Formulae (I),(I-H), (II), (III), (IV), (IV-H), (V), and (VI), or Salts, Solvates, orProdrugs Thereof

In an embodiment, a method of making a compound or derivative havingformula (2), or a salt thereof, can include the steps of:

(a) providing a compound or derivative having formula (2a), or a saltthereof, wherein when R¹⁴ of the compound or derivative having formula(2a), or salt thereof, is methyl, then X′ of the compound or derivativehaving formula (2), or salt thereof, is not acetoxy, and wherein whenR¹⁴ of the compound or derivative having formula (2a), or salt thereof,is phenyl, then X′ of the compound or derivative having formula (2), orsalt thereof, is not benzoxy;

(b) treating the compound or derivative having formula (2a), or saltthereof, with at least a stoichiometric amount of a Brønsted acid or anucleophilic substitution reagent, optionally generated in situ from analcohol and an acyl chloride, in the presence of at least a molarequivalent amount of a polar organic solvent co-reagent;

(c) processing the compound or derivative having formula (2a), or saltthereof, the Brønsted acid or nucleophilic substitution reagent,optionally generated in situ from an alcohol and an acyl chloride, andthe polar organic solvent co-reagent so as to produce the compound orderivative having formula (2), or salt thereof;

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted compound or derivativehaving formula (2a), or salt thereof; and

(d) isolating the compound or derivative having formula (2), or saltthereof.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing under sealed conditions, milling, grinding, andextruding. Liquid-assisted mixing under sealed conditions may beperformed between about 5 Hz and about 50 Hz for about 1 min to about500 min, preferably between about 10 Hz and about 40 Hz for about 15 minto about 180 min, and most preferably between about 20 Hz and about 30Hz for about 60 min to about 120 min. Grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (2), or salt thereof, under almost solventlessconditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (2),or salt thereof, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety).

In another embodiment, a method of making a compound or derivativehaving formula (2), or a salt thereof, can include the steps of:

(a) providing a compound or derivative having formula (2a), or a saltthereof wherein when R¹⁴ of the compound or derivative having formula(2a), or salt thereof, is methyl, then X′ of the compound or derivativehaving formula (2), or salt thereof, is not acetoxy, and wherein whenR¹⁴ of the compound or derivative having formula (2a), or salt thereof,is phenyl, then X′ of the compound or derivative having formula (2), orsalt thereof;

(b) treating the compound or derivative having formula (2a), or saltthereof, with a (1<x<10) equivalent amount of a nucleophilicsubstitution reagent, optionally generated in situ by reacting an acylchloride with an alcohol in stoichiometrically equivalent molar amountsand in the presence of a molar (0<x<10) equivalent amount of a polarorganic organic solvent co-reagent;

(c) processing the compound or derivative having formula (2a), or saltthereof, the nucleophilic substitution reagent, and the polar organicsolvent co-reagent, so as to produce the compound or derivative havingformula (2), or salt thereof;

optionally, (c1) evaporating any volatile by-products resulting from theprocessing step under reduced pressure and temperature-controlledconditions; and

(d) isolating the compound or derivative having formula (2), or saltthereof.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (2), or salt thereof, under almost solventlessconditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (2),or salt thereof, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In an embodiment, a method of making a compound or derivative havingformula (I), or a salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta), can include the steps of:

(a) providing a compound or derivative having formula (2), or a saltthereof;

(b) treating the compound or derivative having formula (2), or saltthereof, with a molar equivalent amount of a compound or derivativehaving formula (1), or a salt thereof;

optionally, (b1) treating the compound or derivative having formula (2),or salt thereof, and the compound or derivative having formula (1), orsalt thereof, with a molar equivalent amount of TMSOTf;

(c) processing the compound or derivative having formula (2), or saltthereof, the compound or derivative having formula (1), or salt thereof,and, optionally, the TMSOTf so as to produce the compound or derivativehaving formula (I), or salt, solvate, or prodrug thereof, optionallyproduced in a particular anomeric ratio (alpha/beta);

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted compound or derivativehaving formula (2), or salt thereof;

optionally, (c3) adding acetone;

optionally, (c4) separately isolating unreacted compound or derivativehaving formula (1), or salt thereof; and

(d) isolating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (I), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta).

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (I),or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta) can be a polar organic solvent from among,for example, preferably, the Class 2 Residual Solvents listed in Table2, or optionally, for non-human use, the Class 3 Residual Solventslisted in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>),incorporated by reference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (I), or a salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),can include the steps of:

(a) adding a volume of methanol and water in a 95:5 weight:weight ratioto the compound or derivative having formula (I), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),at room temperature, so as to dissolve approximately 15% of the compoundor derivative having formula (I), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta), in the volume ofmethanol and water;

(b) stirring the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), at 50° C. until all of the compound or derivative havingformula (I), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta), apparently dissolves in thevolume of methanol and water;

(c) cooling the solution of the compound or derivative having formula(I), or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), in the volume of methanol and water, to−10° C. with stirring so as to precipitate the crystalline form of thecompound or derivative having formula (I), or salt, solvate, or prodrugthereof, optionally in a particular anomeric ratio (alpha/beta);

(d) filtering the volume of methanol and water and the crystalline formof the compound or derivative having formula (I), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),so as to isolate the crystalline form of the compound or derivativehaving formula (I), or salt, solvate, or prodrug thereof, optionally ina particular anomeric ratio (alpha/beta); and

(e) drying the crystalline form of the compound or derivative havingformula (I), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta).

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (I), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta).

In another embodiment, a method of making a compound or derivativehaving formula (I), or a salt, solvate, or prodrug thereof, optionallyin a particular anomeric ratio (alpha/beta), can include the steps of:

(a) providing riboside tetraacetate;

(b) treating the riboside tetraacetate with a molar equivalent amount ofa compound or derivative having formula (1), or a salt thereof;

optionally, (b1) treating the riboside tetraacetate and the compound orderivative having formula (1), or salt thereof, with a molar equivalentamount of TMSOTf;

(c) processing the riboside tetraacetate, the compound or derivativehaving formula (1), or salt thereof, and, optionally, the TMSOTf so asto produce the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally produced in a particularanomeric ratio (alpha/beta);

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted riboside tetraacetate;

optionally, (c3) adding acetone;

optionally, (c4) separately isolating unreacted compound or derivativehaving formula (1), or salt thereof; and

(d) isolating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (I), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta).

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (I),or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), can be a polar organic solvent from among,for example, preferably, the Class 2 Residual Solvents listed in Table2, or optionally, for non-human use, the Class 3 Residual Solventslisted in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>),incorporated by reference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (I), or a salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),can include the steps of:

(a) adding a volume of methanol and water in a 95:5 weight:weight ratioto the compound or derivative having formula (I), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),at room temperature, so as to dissolve approximately 15% of the compoundor derivative having formula (I), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta), in the volume ofmethanol and water;

(b) stirring the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), at 50° C. until all of the compound or derivative havingformula (I), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta), apparently dissolves in thevolume of methanol and water;

(c) cooling the solution of the compound or derivative having formula(I), or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), in the volume of methanol and water, to−10° C. with stirring so as to precipitate the crystalline form of thecompound or derivative having formula (I), or salt, solvate, or prodrugthereof, optionally in a particular anomeric ratio (alpha/beta);

(d) filtering the volume of methanol and water and the crystalline formof the compound or derivative having formula (I), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),so as to isolate the crystalline form of the compound or derivativehaving formula (I), or salt, solvate, or prodrug thereof, optionally ina particular anomeric ratio (alpha/beta); and

(e) drying the crystalline form of the compound or derivative havingformula (I), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta).

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (I), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta).

In yet another embodiment, a method of making a compound or derivativehaving formula (I), or a salt, solvate, or prodrug thereof, optionallyin a particular anomeric ratio (alpha/beta), can include the steps of:

(a) providing a compound or derivative having formula (1), or a saltthereof;

optionally, (a1) treating the compound or derivative having formula (1),or salt thereof, with excess trimethylsilylating reagent(s), and,optionally, heating the compound or derivative having formula (1), orsalt thereof, and the trimethylsilylating reagent(s), to reflux forabout 12 hours so as to produce a compound or derivative having formula(1), or salt thereof, optionally wherein each R¹ is a TMS group;

optionally, (a2) cooling the mixture to room temperature;

optionally, (a3) removing the trimethylsilylating reagent(s);

(b) treating the compound or derivative having formula (1), or saltthereof, optionally wherein each R¹ is a TMS group, with a molarequivalent amount of a compound or derivative having formula (2), or asalt thereof, in an organic solvent co-reagent;

optionally, (b1) treating the compound or derivative having formula (1),or salt thereof, optionally wherein each R¹ is a TMS group, and thecompound or derivative having formula (2), or salt thereof, in anorganic solvent co-reagent, with a molar equivalent amount of TMSOTf;

(c) processing the compound or derivative having formula (1), or saltthereof, optionally wherein each R¹ is a TMS group, the compound orderivative having formula (2), or salt thereof, optionally, the TMSOTf,and the organic solvent co-reagent so as to produce the compound orderivative having formula (I), or salt, solvate, or prodrug thereof,optionally wherein each R¹ is a TMS group, optionally produced in aparticular anomeric ratio (alpha/beta);

(d) adding water to, optionally, the compound or derivative havingformula (1), or salt thereof, optionally wherein each R¹ is a TMS group,optionally, the compound or derivative having formula (2), or saltthereof, optionally, the TMSOTf, the organic solvent co-reagent, and thecompound or derivative having formula (I), or salt, solvate, or prodrugthereof, optionally wherein each R¹ is a TMS group, optionally in aparticular anomeric ratio (alpha/beta);

optionally, (d1) adding saturated NaHCO₃ solution to, optionally, thecompound or derivative having formula (1), or salt thereof, optionallywherein each R¹ is a TMS group, optionally, the compound or derivativehaving formula (2), or salt thereof, optionally, the TMSOTf, the organicsolvent co-reagent, and the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, optionally wherein each R¹ is aTMS group, optionally in a particular anomeric ratio (alpha/beta), andwater;

optionally, (d2) adjusting the pH of the aqueous phase;

optionally, (d3) separating the organic phase from the aqueous phase;

(e) freeze-drying the aqueous phase to provide the compound orderivative having formula (I), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta);

optionally, (e1) dissolving the compound or derivative having formula(I), or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), in methanol in a gas pressure tube;

optionally, (e2) cooling the solution of the compound or derivativehaving formula (I), or salt, solvate, or prodrug thereof, optionally ina particular anomeric ratio (alpha/beta), in methanol to −78° C.;

optionally, (e3) bubbling ammonia gas into the solution of the compoundor derivative having formula (I), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta), in methanol;

optionally, (e4) sealing the pressure tube;

optionally, (e5) raising the temperature to −20° C.;

optionally, (e6) cooling the pressure tube at −20° C. for about 12 hoursto about 4 days, so as to produce a compound or derivative havingformula (I), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen;

optionally, (e7) unsealing the gas pressure tube; and

optionally, (e8) isolating the compound or derivative having formula(I), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (I), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta).

The organic solvent co-reagent employed in the above method of making acompound or derivative having formula (I), or salt, solvate, or prodrugthereof, optionally in a particular anomeric ratio (alpha/beta), can bea polar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (I), or a salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),can include the steps of:

(a) dissolving the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), in a volume of methanol;

(b) adding a volume of acetone, of an equal volume to the volume ofmethanol, to the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), in the volume of methanol;

(c) precipitating the compound or derivative having formula (I), orsalt, solvate, or prodrug thereof, optionally in a particular anomericratio (alpha/beta);

(d) isolating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta); and

(e) washing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), with cold methanol.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (I), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta).

In yet another embodiment, a method of making a compound or derivativehaving formula (I), or a salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl,optionally in a particular anomeric ratio (alpha/beta), can include thesteps of:

(a) providing a compound or derivative having formula (2), or a saltthereof;

(b) treating the compound or derivative having formula (2), or saltthereof, with a molar equivalent amount of a compound or derivativehaving formula (1), or a salt thereof;

optionally, (b1) treating the compound or derivative having formula (2),or salt thereof, and the compound or derivative having formula (1), orsalt thereof, with a molar equivalent amount of TMSOTf;

(c) processing the compound or derivative having formula (2), or saltthereof, the compound or derivative having formula (1), or salt thereof,and, optionally, the TMSOTf so as to produce the compound or derivativehaving formula (I), or salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and R′ is methyl or —C₁alkyl, optionallyproduced in a particular anomeric ratio (alpha/beta);

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted compound or derivativehaving formula (2), or salt thereof;

optionally, (c3) adding acetone;

optionally, (c4) separately isolating unreacted compound or derivativehaving formula (1), or salt thereof; and

(d) isolating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta).

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each—C(O)R′, and wherein R′ is methyl or —C₁alkyl, optionally in aparticular anomeric ratio (alpha/beta), can be a polar organic solventfrom among, for example, preferably, the Class 2 Residual Solventslisted in Table 2, or optionally, for non-human use, the Class 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (I), or a salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl,optionally in a particular anomeric ratio (alpha/beta), can include thesteps of:

(a) providing riboside tetraacetate;

(b) treating the riboside tetraacetate with a stoichiometricallyequivalent amount of a compound or derivative having formula (1), or asalt thereof;

optionally, (b1) treating the riboside tetraacetate and the compound orderivative having formula (1), or salt thereof, with a molar equivalentamount of TMSOTf;

(c) processing the riboside tetraacetate, compound or derivative havingformula (1), or salt thereof, and, optionally, the TMSOTf so as toproduce the compound or derivative having formula (I), or salt, solvate,or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and whereinR′ is methyl or —C₁alkyl, optionally produced in a particular anomericratio (alpha/beta);

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted riboside tetraacetate;

optionally, (c3) adding acetone;

optionally, (c4) separately isolating unreacted compound or derivativehaving formula (1), or salt thereof; and

(d) isolating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, optionally in a particularanomeric ratio.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta).

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each—C(O)R′, and wherein R′ is methyl or —C₁alkyl, optionally in aparticular anomeric ratio (alpha/beta), can be a polar organic solventfrom among, for example, preferably, the Class 2 Residual Solventslisted in Table 2, or optionally, for non-human use, the Class 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (I), or a salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl,optionally in a particular anomeric ratio (alpha/beta), can include thesteps of:

(a) providing a compound or derivative having formula (1), or a saltthereof;

optionally, (a1) treating the compound or derivative having formula (1),or salt thereof, with excess trimethylsilylating reagent(s), and,optionally, heating the compound or derivative having formula (1), orsalt thereof, and the trimethylsilylating reagent(s), to reflux forabout 12 hours so as to produce a compound or derivative having formula(1), or salt thereof, optionally wherein each R¹ is a TMS group;

optionally, (a3) cooling the mixture to room temperature;

optionally, (a4) removing the trimethylsilylating reagent(s);

(b) treating the compound or derivative having formula (1), or saltthereof, optionally wherein each R¹ is a TMS group, with a molarequivalent amount of a compound or derivative having formula (2), or asalt thereof, in an organic solvent co-reagent;

optionally, (b1) treating the compound or derivative having formula (1),or salt thereof, optionally wherein each R¹ is a TMS group, the compoundor derivative having formula (2), or salt thereof, in an organic solventco-reagent, with a molar equivalent amount of TMSOTf;

(c) processing the compound or derivative having formula (1), or saltthereof, optionally wherein each R¹ is a TMS group, the compound orderivative having formula (2), or salt thereof, optionally, the TMSOTf,and the organic solvent co-reagent so as to produce the compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally wherein each R¹ is a TMS group, optionally producedin a particular anomeric ratio (alpha/beta);

(d) adding water to, optionally, the compound or derivative havingformula (1), or salt thereof, optionally wherein each R¹ is a TMS group,optionally, the compound or derivative having formula (2), or saltthereof, optionally, the TMSOTf, the organic solvent co-reagent, and thecompound or derivative having formula (I), or salt, solvate, or prodrugthereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ ismethyl or —C₁alkyl, optionally wherein each R¹ is a TMS group,optionally in a particular anomeric ratio (alpha/beta);

optionally, (d1) adding saturated NaHCO₃ solution to, optionally, thecompound or derivative having formula (1), or salt thereof, optionallywherein each R¹ is a TMS group, optionally, the compound or derivativehaving formula (2), or salt thereof, optionally, the TMSOTf, the organicsolvent co-reagent, and the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each—C(O)R′, and wherein R′ is methyl or —C₁alkyl, optionally wherein eachR¹ is a TMS group, optionally in a particular anomeric ratio(alpha/beta), and water;

optionally, (d2) adjusting the pH of the aqueous phase;

optionally, (d3) separating the organic phase from the aqueous phase;and

(e) freeze-drying the aqueous phase to provide the compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta).

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta).

The organic solvent co-reagent employed in the above method of making acompound of derivative having formula (I), or salt, solvate, or prodrugthereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ ismethyl or —C₁alkyl, optionally in a particular anomeric ratio(alpha/beta), can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In an embodiment, a method of making a compound or derivative havingformula (Ia), or a salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta), can include the steps of:

(a) providing a compound or derivative having formula (2), or a saltthereof;

(b) treating the compound or derivative having formula (2), or saltthereof, with a molar equivalent amount of a compound or derivativehaving formula (1a), or a salt thereof;

optionally, (b1) treating the compound or derivative having formula (2),or salt thereof, and the compound or derivative having formula (1a), orsalt thereof, with a molar equivalent amount of TMSOTf;

(c) processing the compound or derivative having formula (2), or saltthereof, the compound or derivative having formula (1a), or saltthereof, and, optionally, the TMSOTf so as to produce the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,optionally produced in a particular anomeric ratio (alpha/beta);

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted compound or derivativehaving formula (2), or salt thereof;

optionally, (c3) adding acetone;

optionally, (c4) separately isolating unreacted compound or derivativehaving formula (1a), or salt thereof; and

(d) isolating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta).

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), can be a polar organic solvent from among,for example, preferably, the Class 2 Residual Solvents listed in Table2, or optionally, for non-human use, the Class 3 Residual Solventslisted in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>),incorporated by reference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of acompound or derivative having formula (Ia), or a salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),can include the steps of:

(a) adding a volume of methanol and water in a 95:5 weight:weight ratioto the compound or derivative having formula (Ia), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),at room temperature, so as to dissolve approximately 15% of the compoundor derivative having formula (Ia), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta), in the volume ofmethanol and water;

(b) stirring the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), at 50° C. until all of the compound or derivative havingformula (Ia), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta), apparently dissolves in thevolume of methanol and water;

(c) cooling the solution of the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), in the volume of methanol and water, to−10° C. with stirring so as to precipitate the crystalline form of thecompound or derivative having formula (Ia), or salt, solvate, or prodrugthereof, optionally in a particular anomeric ratio (alpha/beta);

(d) filtering the volume of methanol and water and the crystalline formof the compound or derivative having formula (Ia), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),so as to isolate the crystalline form of the compound or derivativehaving formula (Ia), or salt, solvate, or prodrug thereof, optionally ina particular anomeric ratio (alpha/beta); and

(e) drying the crystalline form of the compound or derivative havingformula (Ia), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta).

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (Ia), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta).

In another embodiment, a method of making a compound or derivativehaving formula (Ia), or a salt, solvate, or prodrug thereof, optionallyin a particular anomeric ratio (alpha/beta), can include the steps of:

(a) providing riboside tetraacetate;

(b) treating the riboside tetraacetate with a molar equivalent amount ofa compound or derivative having formula (1a), or a salt thereof;

optionally, (b1) treating the riboside tetraacetate and the compound orderivative having formula (1a), or salt thereof, with a molar equivalentamount of TMSOTf;

(c) processing the riboside tetraacetate, the compound or derivativehaving formula (1a), or salt thereof, and, optionally, the TMSOTf so asto produce the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, optionally produced in a particularanomeric ratio (alpha/beta);

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted riboside tetraacetate;

optionally, (c3) adding acetone;

optionally, (c4) separately isolating unreacted compound or derivativehaving formula (1a), or salt thereof; and

(d) isolating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta).

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), can be a polar organic solvent from among,for example, preferably, the Class 2 Residual Solvents listed in Table2, or optionally, for non-human use, the Class 3 Residual Solventslisted in Table 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>),incorporated by reference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (Ia), or a salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),can include the steps of:

(a) adding a volume of methanol and water in a 95:5 weight:weight ratioto the compound or derivative having formula (Ia), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),at room temperature, so as to dissolve approximately 15% of the compoundor derivative having formula (Ia), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta), in the volume ofmethanol and water;

(b) stirring the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), at 50° C. until all of the compound or derivative havingformula (Ia), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta), apparently dissolves in thevolume of methanol and water;

(c) cooling the solution of the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), in the volume of methanol and water, to−10° C. with stirring so as to precipitate the crystalline form of thecompound or derivative having formula (Ia), or salt, solvate, or prodrugthereof, optionally in a particular anomeric ratio (alpha/beta);

(d) filtering the volume of methanol and water and the crystalline formof the compound or derivative having formula (Ia), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),so as to isolate the crystalline form of the compound or derivativehaving formula (Ia), or salt, solvate, or prodrug thereof, optionally ina particular anomeric ratio (alpha/beta); and

(e) drying the crystalline form of the compound or derivative havingformula (Ia), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta).

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (Ia), or a salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta).

In yet another embodiment, a method of making a compound or derivativehaving formula (Ia), or a salt, solvate, or prodrug thereof, optionallyin a particular anomeric ratio (alpha/beta), can include the steps of:

(a) providing a compound or derivative having formula (1a), or a saltthereof;

optionally, (a1) treating the compound or derivative having formula(1a), or salt thereof, with excess trimethylsilylating reagent(s), and,optionally, heating the compound or derivative having formula (1a), orsalt thereof, and the trimethylsilylating reagent(s), to reflux forabout 12 hours so as to produce a compound or derivative having formula(1a), or salt thereof, optionally wherein R¹ is a TMS group;

optionally, (a2) cooling the mixture to room temperature;

optionally, (a3) removing the trimethylsilylating reagent(s);

(b) treating the compound or derivative having formula (1a), or saltthereof, optionally wherein R¹ is a TMS group, with a molar equivalentamount of a compound or derivative having formula (2), or a saltthereof, in an organic solvent co-reagent;

optionally, (b1) treating the compound or derivative having formula(1a), or salt thereof, wherein R¹ is a TMS group, with a molarequivalent amount of a compound or derivative having formula (2), orsalt thereof, in an organic solvent co-reagent, with a molar equivalentamount of TMSOTf;

(c) processing the compound or derivative having formula (1a), or saltthereof, optionally wherein R¹ is a TMS group, the compound orderivative having formula (2), or salt thereof, optionally, the TMSOTf,and the organic solvent co-reagent so as to produce the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,optionally wherein R¹ is a TMS group, optionally produced in aparticular anomeric ratio (alpha/beta);

(d) adding water to, optionally, the compound or derivative havingformula (1a), or salt thereof, optionally wherein R¹ is a TMS group,optionally, the compound or derivative having formula (2), or saltthereof, optionally, the TMSOTf, the organic solvent co-reagent, and thecompound or derivative having formula (Ia), or salt, solvate, or prodrugthereof, optionally wherein R¹ is a TMS group, optionally in aparticular anomeric ratio (alpha/beta);

optionally, (d1) adding saturated NaHCO₃ solution to, optionally, thecompound or derivative having formula (1a), or salt thereof, optionallywherein R¹ is a TMS group, optionally, the compound or derivative havingformula (2), or salt thereof, optionally, the TMSOTf, the organicsolvent co-reagent, and the compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, optionally wherein R¹ is a TMSgroup, optionally in a particular anomeric ratio (alpha/beta), andwater;

optionally, (d2) adjusting the pH of the aqueous phase;

optionally, (d3) separating the organic phase from the aqueous phase;

(e) freeze-drying the aqueous phase to provide the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta);

optionally, (e1) dissolving the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), in methanol in a gas pressure tube;

optionally, (e2) cooling the solution of the compound or derivativehaving formula (Ia), or salt, solvate, or prodrug thereof, optionally ina particular anomeric ratio (alpha/beta), in methanol to −78° C.;

optionally, (e3) bubbling ammonia gas into the solution of the compoundor derivative having formula (Ia), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta), in methanol;

optionally, (e4) sealing the pressure tube;

optionally, (e5) raising the temperature to −20° C.;

optionally, (e6) cooling the pressure tube at −20° C. for about 12 hoursto about 4 days, so as to produce a compound or derivative havingformula (Ia), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen;

optionally, (e7) unsealing the gas pressure tube; and

optionally, (g8) isolating the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta).

The organic solvent co-reagent employed in the above method of making acompound or derivative having formula (Ia), or salt, solvate, or prodrugthereof, optionally in a particular anomeric ratio (alpha/beta), can bea polar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467), incorporated by reference herein inits entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (Ia), or a salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta),can include the steps of:

(a) dissolving the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), in a volume of methanol;

(b) adding a volume of acetone, of an equal volume to the volume ofmethanol, to the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), in the volume of methanol;

(c) precipitating the crystalline form of the compound or derivativehaving formula (Ia), or salt, solvate, or prodrug thereof, optionally ina particular anomeric ratio (alpha/beta);

(d) isolating the crystalline form of the compound or derivative havingformula (Ia), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta); and

(e) washing the crystalline form of the compound or derivative havingformula (Ia), or salt, solvate, or prodrug thereof, optionally in aparticular anomeric ratio (alpha/beta), with cold methanol.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (Ia), or salt, solvate, orprodrug thereof, optionally in a particular anomeric ratio (alpha/beta).

In yet another embodiment, a method of making a compound or derivativehaving formula (Ia), or a salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl,optionally in a particular anomeric ratio (alpha/beta), can include thesteps of:

(a) providing a compound or derivative having formula (2), or a saltthereof;

(b) treating the compound or derivative having formula (2), or saltthereof, with a molar equivalent amount of a compound or derivativehaving formula (1a), or a salt thereof;

optionally, (b1) treating the compound or derivative having formula (2),or salt thereof, and the compound or derivative having formula (1a), orsalt thereof, with a molar equivalent amount of TMSOTf;

(c) processing the compound or derivative having formula (2), or saltthereof, the compound or derivative having formula (1a), or saltthereof, and, optionally, the TMSOTf so as to produce the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally produced in a particular anomeric ratio(alpha/beta);

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted compound or derivativehaving formula (2), or salt thereof;

optionally, (c3) adding acetone;

optionally, (c4) separately isolating unreacted compound or derivativehaving formula (1a), or salt thereof; and

(d) isolating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, optionally in a particularanomeric ratio.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta).

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each—C(O)R′, and wherein R′ is methyl or —C₁alkyl, optionally in aparticular anomeric ratio (alpha/beta), can be a polar organic solventfrom among, for example, preferably, the Class 2 Residual Solventslisted in Table 2, or optionally, for non-human use, the Class 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (Ia), or a salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl,optionally in a particular anomeric ratio (alpha/beta), can include thesteps of:

(a) providing riboside tetraacetate;

(b) treating the riboside tetraacetate with a stoichiometricallyequivalent amount of a compound or derivative having formula (1a), or asalt thereof;

optionally, (b1) treating the riboside tetraacetate and the compound orderivative having formula (1a), or salt thereof, with a molar equivalentamount of TMSOTf;

(c) processing the riboside tetraacetate, the compound or derivativehaving formula (1a), or salt thereof, and, optionally, the TMSOTf so asto produce the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, optionally produced in aparticular anomeric ratio (alpha/beta);

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted riboside tetraacetate;

optionally, (c3) adding acetone;

optionally, (c4) separately isolating unreacted compound or derivativehaving formula (1a), or salt thereof; and

(d) isolating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, optionally in a particularanomeric ratio.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta).

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each—C(O)R′, and wherein R′ is methyl or —C₁alkyl, optionally in aparticular anomeric ratio (alpha/beta), can be a polar organic solventfrom among, for example, preferably, the Class 2 Residual Solventslisted in Table 2, or optionally, for non-human use, the Class 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (Ia), or a salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl,optionally in a particular anomeric ratio (alpha/beta), can include thesteps of:

(a) providing a compound or derivative having formula (1a), or a saltthereof;

optionally, (a1) treating the compound or derivative having formula(1a), or salt thereof, with excess trimethylsilylating reagent(s), and,optionally, heating the compound or derivative having formula (1a), orsalt thereof, and the trimethylsilylating reagent(s), to reflux forabout 12 hours so as to produce a compound or derivative having formula(1a), or salt thereof, optionally wherein R¹ is a TMS group;

optionally, (a2) cooling the mixture to room temperature;

optionally, (a3) removing the trimethylsilylating reagent(s);

(b) treating the compound or derivative having formula (1a), or saltthereof, optionally wherein R¹ is a TMS group, with a molar equivalentamount of a compound or derivative having formula (2), or a saltthereof, in an organic solvent co-reagent;

optionally, (b1) treating the compound or derivative having formula(1a), or salt thereof, optionally wherein R¹ is a TMS group, with amolar equivalent amount of a compound or derivative having formula (2),or a salt thereof, in an organic solvent co-reagent, with a molarequivalent amount of TMSOTf;

(c) processing the compound or derivative having formula (1a), or saltthereof, optionally wherein R¹ is a TMS group, the compound orderivative having formula (2), or salt thereof, optionally, the TMSOTf,and the organic solvent co-reagent so as to produce the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally wherein R¹ is a TMS group, optionally produced in aparticular anomeric ratio (alpha/beta);

(d) adding water to, optionally, the compound or derivative havingformula (1a), or salt thereof, optionally wherein R¹ is a TMS group,optionally, the compound or derivative having formula (2), or saltthereof, optionally, the TMSOTf, the organic solvent co-reagent, and thecompound or derivative having formula (Ia), or salt, solvate, or prodrugthereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ ismethyl or —C₁alkyl, optionally wherein R¹ is a TMS group, optionally ina particular anomeric ratio (alpha/beta);

optionally, (d1) adding saturated NaHCO₃ solution to, optionally, thecompound or derivative having formula (1a), or salt thereof, optionallywherein R¹ is a TMS group, optionally, the compound or derivative havingformula (2), or salt thereof, optionally, the TMSOTf, the organicsolvent co-reagent, and the compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each—C(O)R′, and wherein R′ is methyl or —C₁alkyl, optionally wherein R¹ isa TMS group, optionally in a particular anomeric ratio (alpha/beta), andwater;

optionally, (d2) adjusting the pH of the aqueous phase;

optionally, (d3) separating the organic phase from the aqueous phase;and

(e) freeze-drying the aqueous phase to provide the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta).

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta).

The organic solvent co-reagent and isolation solvent employed in theabove method of making a compound or derivative having formula (Ia), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each—C(O)R′, and wherein R′ is methyl or —C₁alkyl, optionally in aparticular anomeric ratio (alpha/beta), can be a polar organic solventfrom among, for example, preferably, the Class 2 Residual Solventslisted in Table 2, or optionally, for non-human use, the Class 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In an embodiment, a method of making a compound or derivative havingformula (I-H), or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, optionally in a particularanomeric ratio (alpha/beta);

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with a molar equivalent amount ofan alcohol (e.g., methanol, or ethanol) and at least a sub-molarequivalent amount of a Brønsted inorganic base;

(c) processing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, the alcohol, and the Brønstedinorganic base so as to produce the compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen;

optionally, (c1) neutralizing the Brønsted inorganic base using aconcentrated acid solution under controlled conditions;

optionally, (c2) evaporating any volatile by-products resulting from theprocessing and neutralizing steps;

(d) isolating the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (d1) separately isolating the unreacted compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta); and

optionally, (d2) drying the compound or derivative having formula (I-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (I-H), or a salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, can includethe steps of:

(a) adding a volume of methanol and water in a 95:5 weight:weight ratioto the compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, at roomtemperature, so as to dissolve approximately 15% of the compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, in the volume of methanol andwater;

(b) stirring the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,at 50° C. until all of the compound or derivative having formula (I-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, apparently dissolves in the volume of methanol and water;

(c) cooling the solution of the compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, in the volume of methanol and water, to −10° C. withstirring so as to precipitate the crystalline form of the compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen;

(d) filtering the volume of methanol and water and the crystalline formof the compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, so as toisolate the crystalline form of the compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen; and

(e) drying the crystalline form of the compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

In another embodiment, a method of making a compound or derivativehaving formula (I-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, optionally in a particularanomeric ratio (alpha/beta);

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with molar equivalent amounts(3<x<100) of an alcohol (e.g., methanol, or ethanol) and molarequivalent amounts (x≤20) of a Brønsted inorganic acid;

(c) processing, under sealed conditions, the compound or derivativehaving formula (I), or salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl, thealcohol (e.g., methanol, or ethanol), and the Brønsted inorganic acid soas to produce the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(d) isolating the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (d1) separately isolating the unreacted compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta);

optionally, (d2) washing the compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, with cold alcohol (e.g., methanol, or ethanol); and

optionally, (d3) drying the compound or derivative having formula (I-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (I-H), or a salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, can includethe steps of:

(a) adding a volume of methanol and water in a 95:5 weight:weight ratioto the compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, at roomtemperature, so as to dissolve approximately 15% of the compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, in the volume of methanol andwater;

(b) stirring the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,at 50° C. until all of the compound or derivative having formula (I-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, apparently dissolves in the volume of methanol and water;

(c) cooling the solution of the compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, in the volume of methanol and water, to −10° C. withstirring so as to precipitate the crystalline form of the compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen;

(d) filtering the volume of methanol and water and the crystalline formof the compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, so as toisolate the crystalline form of the compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen; and

(e) drying the crystalline form of the compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

In yet another embodiment, a method of making a compound or derivativehaving formula (I-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, optionally in a particularanomeric ratio (alpha/beta);

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with molar equivalent amounts(3<x<100) of an alcohol (e.g., methanol, or ethanol) and molarequivalent amounts (3≤x<20) of an acyl chloride;

(c) processing, under sealed conditions, the compound or derivativehaving formula (I), or salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl, thealcohol (e.g., methanol, or ethanol), and the acyl chloride so as togenerate HCl in situ and produce the compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen;

(d) isolating the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (d1) separately isolating the unreacted compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta);

optionally, (d2) washing the compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, with cold alcohol (e.g., methanol, or ethanol); and

optionally, (d3) drying the compound or derivative having formula (I-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (I-H), or a salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, can includethe steps of:

(a) adding a volume of methanol and water in a 95:5 weight:weight ratioto the compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, at roomtemperature, so as to dissolve approximately 15% of the compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, in the volume of methanol andwater;

(b) stirring the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,at 50° C. until all of the compound or derivative having formula (I-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, apparently dissolves in the volume of methanol and water;

(c) cooling the solution of the compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, in the volume of methanol and water, to −10° C. withstirring so as to precipitate the crystalline form of the compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen;

(d) filtering the volume of methanol and water and the crystalline formof the compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, so as toisolate the crystalline form of the compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen; and

(e) drying the crystalline form of the compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

In yet another embodiment, a method of making a compound or derivativehaving formula (I-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, optionally in a particular anomericratio (alpha/beta), can include the steps of:

(a) providing a compound or derivative having formula (1), or a saltthereof;

optionally, (a1) treating the compound or derivative having formula (1),or salt thereof, with excess trimethylsilylating reagent(s), and,optionally, heating the compound or derivative having formula (1), orsalt thereof, and the trimethylsilylating reagent(s), to reflux forabout 12 hours so as to produce a compound or derivative having formula(1), or salt thereof, generally wherein each R¹ is a TMS group;

optionally, (a2) cooling the mixture to room temperature;

optionally, (a3) removing the trimethylsilylating reagent(s);

(b) treating the compound or derivative having formula (1), or saltthereof, optionally wherein each R¹ is a TMS group, with a molarequivalent amount of a compound or derivative having formula (2), or asalt thereof, in an organic solvent co-reagent;

optionally, (b1) treating the compound or derivative having formula (1),or salt thereof, optionally wherein each R¹ is a TMS group, with a molarequivalent amount of a compound or derivative having formula (2), or asalt thereof, in an organic solvent co-reagent, with a molar equivalentamount of TMSOTf;

(c) processing the compound or derivative having formula (1), or saltthereof, optionally wherein each R¹ is a TMS group, the compound orderivative having formula (2), or salt thereof, optionally, the TMSOTf,and the organic solvent co-reagent so as to produce a compound orderivative having formula (I), or salt, solvate, or prodrug thereof,optionally wherein each R¹ is a TMS group, optionally produced in aparticular anomeric ratio (alpha/beta);

(d) adding water to, optionally, the compound or derivative havingformula (1), or salt thereof, optionally wherein each R¹ is a TMS group,optionally, the compound or derivative having formula (2), or saltthereof, optionally, the TMSOTf, the organic solvent co-reagent, and thecompound or derivative having formula (I), or salt, solvate, or prodrugthereof, optionally wherein each R¹ is a TMS group, optionally in aparticular anomeric ratio (alpha/beta);

optionally, (d1) adding saturated NaHCO₃ solution to, optionally, thecompound or derivative having formula (1), or salt thereof, optionallywherein each R¹ is a TMS group, optionally, the compound or derivativehaving formula (2), or salt thereof, optionally, the TMSOTf, the organicsolvent co-reagent, and the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, optionally wherein each R¹ is aTMS group, optionally in a particular anomeric ratio (alpha/beta), andwater;

optionally, (d2) adjusting the pH of the aqueous phase;

optionally, (d3) separating the organic phase from the aqueous phase;

(e) freeze-drying the aqueous phase to provide the compound orderivative having formula (I), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta);

(f) dissolving the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), in methanol in a gas pressure tube;

(g) cooling the solution of the compound or derivative having formula(I), or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), in methanol to −78° C.;

(h) bubbling ammonia gas into the solution of the compound or derivativehaving formula (I), or salt, solvate, or prodrug thereof, optionally ina particular anomeric ratio (alpha/beta), in methanol, so as to producethe compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally ina particular anomeric ratio (alpha/beta);

(i) sealing the pressure tube;

(j) raising the temperature to −20° C.;

(k) cooling the pressure tube at −20° C. for about 12 hours to about 4days;

(l) unsealing the gas pressure tube; and

(m) isolating the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally in a particularanomeric ratio (alpha/beta).

The organic solvent co-reagent employed in the above method of making acompound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally ina particular anomeric ratio (alpha/beta), can be a polar organic solventfrom among, for example, preferably, the Class 2 Residual Solventslisted in Table 2, or optionally, for non-human use, the Class 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (I-H), or a salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally ina particular anomeric ratio (alpha/beta), can include the steps of:

(a) dissolving the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,optionally in a particular anomeric ratio (alpha/beta), in a volume ofmethanol;

(b) adding a volume of acetone, of an equal volume to the volume ofmethanol, to the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,optionally in a particular anomeric ratio (alpha/beta), in the volume ofmethanol;

(c) precipitating the crystalline form of the compound or derivativehaving formula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each hydrogen, optionally in a particular anomeric ratio(alpha/beta);

(d) isolating the crystalline form of the compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen, optionally in a particular anomeric ratio(alpha/beta); and

(e) washing the crystalline form of the compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen, optionally in a particular anomeric ratio(alpha/beta), with cold methanol.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally ina particular anomeric ratio (alpha/beta).

In an embodiment, a method of making a compound or derivative havingformula (Ia-H), or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, optionally in a particularanomeric ratio (alpha/beta);

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with a molar equivalent amount ofan alcohol (e.g., methanol, or ethanol) and at least a sub-molarequivalent amount of a Brønsted inorganic base;

(c) processing the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, the alcohol, and the Brønstedinorganic base so as to produce the compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen;

optionally, (c1) neutralizing the base using a concentrated acidsolution under controlled conditions;

optionally, (c2) evaporating volatile by-products resulting from theprocessing and neutralizing steps from the neutralized reaction mixture;

(d) isolating the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (d1) separately isolating the unreacted compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta); and

optionally, (d2) drying the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (Ia-H), or a salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, can includethe steps of:

(a) adding a volume of methanol and water in a 95:5 weight:weight ratioto the compound or derivative having formula (Ia-H), or salt, solvate,or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, at roomtemperature, so as to dissolve approximately 15% of the compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, in the volume of methanol andwater;

(b) stirring the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,at 50° C. until all of the compound or derivative having formula (Ia-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, apparently dissolves in the volume of methanol and water;

(c) cooling the solution of the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, in the volume of methanol and water, to −10° C. withstirring so as to precipitate the crystalline form of the compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen;

(d) filtering the volume of methanol and water and the crystalline formof the compound or derivative having formula (Ia-H), or salt, solvate,or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, so as toisolate the crystalline form of the compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen; and

(e) drying the crystalline form of the compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (Ia-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

In another embodiment, a method of making a compound or derivativehaving formula (Ia-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, optionally in a particularanomeric ratio (alpha/beta);

(b) treating the compound or derivative having (Ia), or salt, solvate,or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and whereinR′ is methyl or —C₁alkyl, with molar equivalent amounts (3<x<100) ofalcohol (e.g., methanol, or ethanol) and molar equivalent amounts (x≤20)of a Brønsted inorganic acid;

(c) processing, under sealed conditions, the compound or derivativehaving formula (Ia), or salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl, thealcohol (e.g., methanol, or ethanol), and the Brønsted inorganic acid soas to produce the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(d) isolating the compound or derivative having formula (Ia-H), or salt,solvate, or produg thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (d1) separately isolating the unreacted compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta);

optionally, (d2) washing the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, with cold alcohol (e.g., methanol, or ethanol); and

optionally, (d3) drying the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (Ia-H), or a salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, can includethe steps of:

(a) adding a volume of methanol and water in a 95:5 weight:weight ratioto the compound or derivative having formula (Ia-H), or salt, solvate,or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, at roomtemperature, so as to dissolve approximately 15% of the compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, in the volume of methanol andwater;

(b) stirring the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,at 50° C. until all of the compound or derivative having formula (Ia-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, apparently dissolves in the volume of methanol and water;

(c) cooling the solution of the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, in the volume of methanol and water, to −10° C. withstirring so as to precipitate the crystalline form of the compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen;

(d) filtering the volume of methanol and water and the crystalline formof the compound or derivative having formula (Ia-H), or salt, solvate,or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, so as toisolate the crystalline form of the compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen; and

(e) drying the crystalline form of the compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (Ia-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

In yet another embodiment, a method of making a compound or derivativehaving formula (Ia-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, optionally in a particularanomeric ratio (alpha/beta);

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with molar equivalent amounts(3<x<100) of an alcohol (e.g., methanol, or ethanol) and molarequivalent amounts (3≤x<20) of an acyl chloride;

(c) processing, under sealed conditions, the compound having formula(Ia), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach —C(O)R′, and wherein R′ is methyl or —C₁alkyl, the alcohol (e.g.,methanol, or ethanol), and the acyl chloride so as to generate HCl insitu and produce the compound or derivative having formula (Ia-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

(d) isolating the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (d1) separately isolating the unreacted compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, optionally in a particular anomeric ratio (alpha/beta);

optionally, (d2) washing the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, with cold alcohol (e.g., methanol, or ethanol); and

optionally, (d3) drying the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (Ia-H), or a salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, can includethe steps of:

(a) adding a volume of methanol and water in a 95:5 weight:weight ratioto the compound or derivative having formula (Ia-H), or salt, solvate,or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, at roomtemperature, so as to dissolve approximately 15% of the compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, in the volume of methanol andwater;

(b) stirring the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,at 50° C. until all of the compound or derivative having formula (Ia-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, apparently dissolves in the volume of methanol and water;

(c) cooling the solution of the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, in the volume of methanol and water, to −10° C. withstirring so as to precipitate the crystalline form of the compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen;

(d) filtering the volume of methanol and water and the crystalline formof the compound or derivative having formula (Ia-H), or salt, solvate,or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, so as toisolate the crystalline form of the compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen; and

(e) drying the crystalline form of the compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (Ia-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen.

In yet another embodiment, a method of making a compound or derivativehaving formula (Ia-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, optionally in a particular anomericratio (alpha/beta), can include the steps of:

(a) providing a compound or derivative having formula (1a), or a saltthereof;

optionally, (a1) treating the compound or derivative having formula(1a), or salt thereof, with excess trimethylsilylating reagent(s), and,optionally, heating the compound or derivative having formula (1a), orsalt thereof, and the trimethylsilylating reagent(s), to reflux forabout 12 hours so as to produce a compound or derivative having formula(1a), or salt thereof, optionally wherein R¹ is a TMS group;

optionally, (a2) cooling the mixture to room temperature;

optionally, (a3) removing the trimethylsilylating reagent(s);

(b) treating the compound or derivative having formula (1a), or saltthereof, optionally wherein R¹ is a TMS group, with a molar equivalentamount of a compound or derivative having formula (2), or a saltthereof, in an organic solvent co-reagent;

optionally, (b1) treating the compound or derivative having formula(1a), or salt thereof, optionally wherein R¹ is a TMS group, and thecompound or derivative having formula (2), or salt thereof, in anorganic solvent co-reagent, with a molar equivalent amount of TMSOTf;

(c) processing the compound or derivative having formula (1a), or saltthereof, optionally wherein R¹ is a TMS group, the compound orderivative having formula (2), or salt thereof, optionally, the TMSOTf,and the organic solvent co-reagent so as to produce a compound orderivative having formula (Ia), or a salt, solvate, or prodrug thereof,optionally wherein R¹ is a TMS group, optionally in a particularanomeric ratio (alpha/beta);

(d) adding water to, optionally, the compound or derivative havingformula (1a), or salt thereof, optionally wherein R¹ is a TMS group,optionally, the compound or derivative having formula (2), or saltthereof, optionally, the TMSOTf, the organic solvent co-reagent, and thecompound or derivative having formula (Ia), or salt, solvate, or prodrugthereof, optionally wherein R¹ is a TMS group, optionally in aparticular anomeric ratio (alpha/beta);

optionally, (d1) adding saturated NaHCO₃ solution to optionally, thecompound or derivative having formula (1a), or salt thereof, optionallywherein R¹ is a TMS group, optionally, the compound or derivative havingformula (2), or salt thereof, optionally, the TMSOTf, the organicsolvent co-reagent, and the compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, optionally wherein R¹ is a TMSgroup, optionally in a particular anomeric ratio (alpha/beta), andwater;

optionally, (d2) adjusting the pH of the aqueous phase;

optionally, (d3) separating the organic phase from the aqueous phase;

(e) freeze-drying the aqueous phase to provide the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,optionally in a particular anomeric ratio (alpha/beta);

(f) dissolving the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), in methanol in a gas pressure tube;

(g) cooling the solution of the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, optionally in a particularanomeric ratio (alpha/beta), in methanol to −78° C.;

(h) bubbling ammonia gas into the solution of the compound or derivativehaving formula (Ia), or salt, solvate, or prodrug thereof, optionally ina particular anomeric ratio (alpha/beta), in methanol, so as to producethe compound or derivative having formula (Ia-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally ina particular anomeric ratio (alpha/beta);

(i) sealing the pressure tube;

(j) raising the temperature to −20° C.;

(k) cooling the pressure tube at −20° C. for about 12 hours to about 4days;

(l) unsealing the gas pressure tube;

and (m) isolating the compound or derivative having formula (Ia-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally in a particularanomeric ratio (alpha/beta).

The organic solvent co-reagent employed in the above method of making acompound or derivative having formula (Ia-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (Ia-H), or a salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally ina particular anomeric ratio (alpha/beta), can include the steps of:

(a) dissolving the compound or derivative having formula (Ia-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, optionally in a particular anomeric ratio (alpha/beta), in avolume of methanol;

(b) adding a volume of acetone, of an equal volume to the volume ofmethanol, to the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,optionally in a particular anomeric ratio (alpha/beta), in the volume ofmethanol;

(c) precipitating the crystalline form of the compound or derivativehaving formula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each hydrogen, optionally in a particular anomeric ratio(alpha/beta);

(d) isolating the crystalline form of the compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen, optionally in a particular anomeric ratio(alpha/beta); and

(e) washing the crystalline form of the compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen, optionally in a particular anomeric ratio(alpha/beta), with cold methanol.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (Ia-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally ina particular anomeric ratio (alpha/beta).

In an embodiment, a method of making a compound or derivative havingformula (II), or a salt, solvate, or prodrug thereof, wherein Y³ isoxygen, can include the steps of:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen;

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with aphosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen, and thephosphorylating reagent, with a (0<x≤20) molar equivalent amount of aBrønsted acid or base;

(c) processing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, the phosphorylatingreagent, and, optionally, the Brønsted acid or base, so as to producethe compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen;

(d) adding, optionally, the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen,optionally, the phosphorylating reagent, optionally, the Brønsted acidor base, and the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (I), or salt, solvate, or prodrug thereof, wherein R⁶ ishydrogen;

(e) isolating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (e1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (II), or a salt, solvate, orprodrug thereof, wherein Y³ is oxygen, can include the steps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of methanol and water, so as to remove any undissolved solids;

(d) adding a volume of acetone to the solution of the compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, in the volume of methanol and water, wherein thevolume of acetone is about 2 to about 5 times the combined volume ofmethanol and water;

(e) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, the volume ofacetone, and the volume of methanol and water at −20° C. so as toprecipitate the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen;

(f) filtering the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, the volume of acetone, and the volume of methanol and water soas to isolate the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen; and

(g) drying the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, an alternative method of making acrystalline form of the compound or derivative having formula (II), or asalt, solvate, or prodrug thereof, wherein Y³ is oxygen, can include thesteps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of methanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water at −20° C. so as to produce an oily layer at thebottom of the volume of methanol and water;

(e) decanting the volume of methanol and water from the oily layer atthe bottom of the volume of methanol and water; and

(f) drying the oily layer at room temperature so as to crystallize thecrystalline form of the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, another alternative method of making acrystalline form of the compound or derivative having formula (II), or asalt, solvate, or prodrug thereof, wherein Y³ is oxygen, can include thesteps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofethanol and water in a 3:2 volume:volume ratio at room temperature,wherein the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, is added in an amountof about 200 milligrams per milliliter of the volume of ethanol andwater;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of ethanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of ethanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, in the volume ofethanol and water, to −10° C. for about 48 hours so as to produce thecrystalline form of the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(e) decanting the volume of ethanol and water from the crystalline formof the compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen, so as to isolate the crystallineform of the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

(f) drying the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In another embodiment, a method of making a compound or derivativehaving formula (II), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen;

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with aphosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen, and thephosphitylating reagent, with a (0<x≤20) molar equivalent amount of aBrønsted acid or base;

(c) processing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, the phosphitylatingreagent, and, optionally, the Brønsted acid or base, so as to produce acompound or derivative having formula (II), or a salt, solvate, orprodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶ is hydrogen, optionally, the phosphitylating reagent,optionally, the Brønsted acid or base, and the compound or derivativehaving formula (II), or salt, solvate, or prodrug thereof, wherein Y³ isabsent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶ is hydrogen, optionally, the phosphitylating reagent,optionally, the Brønsted acid or base, and the compound or derivativehaving formula (II), or salt, solvate, or prodrug thereof, wherein Y³ isabsent, so as to produce the compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (I), or salt, solvate, or prodrugthereof, wherein R⁶ is hydrogen, optionally, the phosphitylating agent,optionally, the Brønsted acid or base, optionally, the compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is absent, and the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, toiced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (g1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (II), or a salt, solvate, orprodrug thereof, wherein Y³ is oxygen, can include the steps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of methanol and water, so as to remove any undissolved solids;

(d) adding a volume of acetone to the solution of the compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, in the volume of methanol and water, wherein thevolume of acetone is about 2 to about 5 times the combined volume ofmethanol and water;

(e) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, the volume ofacetone, and the volume of methanol and water at −20° C. so as toprecipitate the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen;

(f) filtering the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, the volume of acetone, and the volume of methanol and water soas to isolate the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen; and

(g) drying the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, an alternative method of making acrystalline form of the compound or derivative having formula (II), or asalt, solvate, or prodrug thereof, wherein Y³ is oxygen, can include thesteps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of methanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water at −20° C. so as to produce an oily layer at thebottom of the volume of methanol and water;

(e) decanting the volume of methanol and water from the oily layer atthe bottom of the volume of methanol and water; and

(f) drying the oily layer at room temperature so as to crystallize thecrystalline form of the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, another alternative method of making acrystalline form of the compound or derivative having formula (II), or asalt, solvate, or prodrug thereof, wherein Y³ is oxygen, can include thesteps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofethanol and water in a 3:2 volume:volume ratio at room temperature,wherein the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, is added in an amountof about 200 milligrams per milliliter of the volume of ethanol andwater;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of ethanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of ethanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, in the volume ofethanol and water, to −10° C. for about 48 hours so as to produce thecrystalline form of the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(e) decanting the volume of ethanol and water from the crystalline formof the compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen, so as to isolate the crystallineform of the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

(f) drying the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In yet another embodiment, a method of making a compound or derivativehaving formula (II), or a salt, solvate, or prodrug thereof, wherein Y³is absent, can include the steps of:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen;

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with aphosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen, and thephosphitylating reagent, with a (0<x≤20) molar equivalent amount of aBrønsted acid or base;

(c) processing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, the phosphitylatingreagent, and, optionally, the Brønsted acid or base so as to produce thecompound or derivative having formula (II), or salt, solvate, or prodrugthereof, wherein Y³ is absent;

(d) adding, optionally, the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen,optionally, the phosphitylating reagent, optionally, the Brønsted acidor base, and the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is absent, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

(e) isolating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is absent; and

optionally, (e1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is absent, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is absent, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is absent, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (II), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen;

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with aphosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen, and thephosphitylating reagent, with a (0<x≤20) molar equivalent amount of aBrønsted acid or base;

(c) processing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, the phosphitylatingreagent, and, optionally, the Brønsted acid or base so as to produce acompound or derivative having formula (II), or a salt, solvate, orprodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶ is hydrogen, optionally, the phosphitylating reagent,optionally, the Brønsted acid or base, and the compound or derivativehaving formula (II), or salt, solvate, or prodrug thereof, wherein Y³ isabsent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (I), or salt, solvate, or prodrug thereof,wherein R⁶ is hydrogen, optionally, the phosphitylating reagent,optionally, the Brønsted acid or base, and the compound or derivativehaving formula (II), or salt, solvate, or prodrug thereof, wherein Y³ isabsent, so as to produce the compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (I), or salt, solvate, or prodrugthereof, wherein R⁶ is hydrogen, optionally, the phosphitylatingreagent, optionally, the Brønsted acid or base, optionally, the compoundor derivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is absent, and the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, toiced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (g1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (II), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen;

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with athiophosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen, and thethiophosphorylating reagent, with a (0<x≤20) molar equivalent amount ofa Brønsted acid or base;

(c) processing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, thethiophosphorylating reagent, and, optionally, the Brønsted acid or base,so as to produce the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is sulfur;

(d) adding, optionally, the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen,optionally, the thiophosphorylating reagent, optionally, the Brønstedacid or base, and the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is sulfur, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (I), or salt, solvate, or prodrug thereof, wherein R⁶ ishydrogen;

(e) isolating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (e1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (II), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (I-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphorylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted acid or base;

(c) processing the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,the phosphorylating reagent, and, optionally, the Brønsted acid or base,so as to produce the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(d) adding, optionally, the compound or derivative having formula (I-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, optionally, the phosphorylating reagent, optionally, theBrønsted acid or base, and the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, toiced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen; and

(e) isolating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (e1) treating the compound or derivative having formula(II), wherein Y³ is oxygen, with deprotection reagent(s) in a polarorganic solvent co-reagent so as to remove any protecting groups of R⁷,R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (II), or a salt, solvate, orprodrug thereof, wherein Y³ is oxygen, can include the steps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of methanol and water, so as to remove any undissolved solids;

(d) adding a volume of acetone to the solution of the compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, in the volume of methanol and water, wherein thevolume of acetone is about 2 to about 5 times the combined volume ofmethanol and water;

(e) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, the volume ofacetone, and the volume of methanol and water at −20° C. so as toprecipitate the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen;

(f) filtering the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, the volume of acetone, and the volume of methanol and water soas to isolate the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen; and

(g) drying the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, an alternative method of making acrystalline form of a compound or derivative having formula (II), or asalt, solvate, or prodrug thereof, wherein Y³ is oxygen, can include thesteps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of methanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water at −20° C. so as to produce an oily layer at thebottom of the volume of methanol and water;

(e) decanting the volume of methanol and water from the oily layer atthe bottom of the volume of methanol and water; and

(f) drying the oily layer at room temperature so as to crystallize thecrystalline form of the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, another alternative method of making acrystalline form of the compound or derivative having formula (II), or asalt, solvate, or prodrug thereof, wherein Y³ is oxygen, can include thesteps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofethanol and water in a 3:2 volume:volume ratio at room temperature,wherein the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, is added in an amountof about 200 milligrams per milliliter of the volume of ethanol andwater;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of ethanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of ethanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, in the volume ofethanol and water, to −10° C. for about 48 hours so as to produce thecrystalline form of the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(e) decanting the volume of ethanol and water from the crystalline formof the compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen, so as to isolate the crystallineform of the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

(f) drying the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In yet another embodiment, a method of making a compound or derivativehaving formula (II), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (I-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphitylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted acid or base;

(c) processing the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,the phosphitylating reagent, and, optionally, the Brønsted acid or baseso as to produce a compound or derivative having formula (II), or asalt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted acid or base, and thecompound or derivative having formula (II), or salt, solvate, or prodrugthereof, wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted acid or base, and thecompound or derivative having formula (II), or salt, solvate, or prodrugthereof, wherein Y³ is absent, so as to produce the compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally,the phosphitylating reagent, optionally, the Brønsted acid or base,optionally, the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is absent, and the compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (g1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (II), or a salt, solvate, orprodrug thereof, wherein Y³ is oxygen, can include the steps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of methanol and water, so as to remove any undissolved solids;

(d) adding a volume of acetone to the solution of the compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, in the volume of methanol and water, wherein thevolume of acetone is about 2 to about 5 times the combined volume ofmethanol and water;

(e) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, the volume ofacetone, and the volume of methanol and water at −20° C. so as toprecipitate the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen;

(f) filtering the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, the volume of acetone, and the volume of methanol and water soas to isolate the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen; and

(g) drying the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, an alternative method of making acrystalline form of the compound or derivative having formula (II), or asalt, solvate, or prodrug thereof, wherein Y³ is oxygen, can include thesteps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of methanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water at −20° C. so as to produce an oily layer at thebottom of the volume of methanol and water;

(e) decanting the volume of methanol and water from the oily layer atthe bottom of the volume of methanol and water; and

(f) drying the oily layer at room temperature so as to crystallize thecrystalline form of the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, another alternative method of making acrystalline form of the compound or derivative having formula (II), or asalt, solvate, or prodrug thereof, wherein Y³ is oxygen, can include thesteps of:

(a) adding the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofethanol and water in a 3:2 volume:volume ratio at room temperature,wherein the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, is added in an amountof about 200 milligrams per milliliter of the volume of ethanol andwater;

(b) stirring the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofethanol and water so as to dissolve the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of ethanol and water;

(c) filtering the solution of the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, in thevolume of ethanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, in the volume ofethanol and water, to −10° C. for about 48 hours so as to produce thecrystalline form of the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(e) decanting the volume of ethanol and water from the crystalline formof the compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen, so as to isolate the crystallineform of the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

(f) drying the crystalline form of the compound or derivative havingformula (II), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (II), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In yet another embodiment, a method of making a compound or derivativehaving formula (II), or a salt, solvate, or prodrug thereof, wherein Y³is absent, can include the steps of:

(a) providing a compound or derivative having formula (I-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphitylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted acid or base;

(c) processing the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,the phosphitylating reagent, and, optionally, the Brønsted acid or baseso as to produce the compound or derivative having formula (II), orsalt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding, optionally, the compound or derivative having formula (I-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, optionally, the phosphitylating reagent, optionally, theBrønsted acid or base, and the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is absent, toiced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

(e) isolating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is absent; and

optionally, (e1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is absent, withdeprotection agent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is absent, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is absent, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (II), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (I-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphitylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted acid or base;

(c) processing the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,the phosphitylating reagent, and, optionally, the Brønsted acid or baseso as to produce a compound or derivative having formula (II), or asalt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (I-H), wherein R⁶, R⁷, and R⁸ are eachhydrogen, optionally, the phosphitylating reagent, optionally, theBrønsted acid or base, and the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (I-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted acid or base, and thecompound or derivative having formula (II), or salt, solvate, or prodrugthereof, wherein Y³ is absent, so as to produce the compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (I-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally,the phosphitylating reagent, optionally, the Brønsted acid or base,optionally, the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is absent, and the compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (g1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (II), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (I-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a thiophosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the thiophosphorylating reagent, with a (0<x≤20)molar equivalent amount of a Brønsted acid or base;

(c) processing the compound or derivative having formula (I-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,the thiophosphorylating reagent, and, optionally, the Brønsted acid orbase, so as to produce the compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur;

(d) adding, optionally, the compound or derivative having formula (I-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, optionally, the thiophosphorylating reagent, optionally, theBrønsted acid or base, and the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, toiced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (I-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, andR⁸ are each hydrogen;

(e) isolating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (e1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (II), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (II),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In an embodiment, a method of making a compound or derivative havingformula (IIa), or a salt, solvate, or prodrug thereof, wherein Y³ isoxygen, can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen;

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with aphosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen, andthe phosphorylating reagent, with a (0<x≤20) molar equivalent amount ofa Brønsted acid or base;

(c) processing the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, the phosphorylatingreagent, and, optionally, the Brønsted acid or base, so as to producethe compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen;

(d) adding, optionally, the compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen,optionally, the phosphorylating reagent, optionally, the Brønsted acidor base, and the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (Ia), or salt, solvate, or prodrug thereof, wherein R⁶ ishydrogen;

(e) isolating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (e1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection agent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, canbe a polar organic solvent from among, for example, preferably, theClass 2 Residual Solvents listed in Table 2, or optionally, fornon-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S.PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (IIa), or a salt, solvate, orprodrug thereof, wherein Y³ is oxygen, can include the steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of methanol and water, so as to remove any undissolvedsolids;

(d) adding a volume of acetone to the solution of the compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, in the volume of methanol and water, wherein thevolume of acetone is about 2 to about 5 times the combined volume ofmethanol and water;

(e) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, the volume ofacetone, and the volume of methanol and water at −20° C. so as toprecipitate the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen;

(f) filtering the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, the volume of acetone, and the volume of methanol and water soas to isolate the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen; and

(g) drying the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, an alternative method of making acrystalline form of the compound or derivative having formula (IIa), ora salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can includethe steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of methanol and water, so as to remove any undissolvedsolids;

(d) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water at −20° C. so as to produce an oily layer at thebottom of the volume of methanol and water;

(e) decanting the volume of methanol and water from the oily layer atthe bottom of the volume of methanol and water; and

(f) drying the oily layer at room temperature so as to crystallize thecrystalline form of the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, another alternative method of making acrystalline form of the compound or derivative having formula (IIa), ora salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can includethe steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofethanol and water in a 3:2 volume:volume ratio at room temperature,wherein the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, is added in an amountof about 200 milligrams per milliliter of the volume of ethanol andwater;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of ethanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of ethanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, in the volume ofethanol and water, to −10° C. for about 48 hours so as to produce thecrystalline form of the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(e) decanting the volume of ethanol and water from the crystalline formof the compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen, so as to isolate the crystallineform of the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

(f) drying the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In another embodiment, a method of making a compound or derivativehaving formula (IIa), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen;

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with aphosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen, andthe phosphitylating reagent, with a (0<x≤20) molar equivalent amount ofa Brønsted acid or base;

(c) processing the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, the phosphitylatingreagent, and, optionally, the Brønsted acid or base so as to produce acompound or derivative having formula (IIa), or a salt, solvate, orprodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶ is hydrogen, optionally, the phosphitylating reagent,optionally, the Brønsted acid or base, and the compound or derivativehaving formula (IIa), or salt, solvate, or prodrug thereof, wherein Y³is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶ is hydrogen, optionally, the phosphitylating reagent,optionally, the Brønsted acid or base, and the compound or derivativehaving formula (IIa), or salt, solvate, or prodrug thereof, wherein Y³is absent, so as to produce the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (Ia), or salt, solvate, or prodrugthereof, wherein R⁶ is hydrogen, optionally, the phosphitylatingreagent, optionally, the Brønsted acid or base, optionally, the compoundor derivative having formula (IIa), or salt, solvate, or prodrugthereof, wherein Y³ is absent, and the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (g1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, canbe a polar organic solvent from among, for example, preferably, theClass 2 Residual Solvents listed in Table 2, or optionally, fornon-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S.PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (IIa), or a salt, solvate, orprodrug thereof, wherein Y³ is oxygen, can include the steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of methanol and water, so as to remove any undissolvedsolids;

(d) adding a volume of acetone to the solution of the compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, in the volume of methanol and water, wherein thevolume of acetone is about 2 to about 5 times the combined volume ofmethanol and water;

(e) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, the volume ofacetone, and the volume of methanol and water at −20° C. so as toprecipitate the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen;

(f) filtering the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, the volume of acetone, and the volume of methanol and water soas to isolate the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen; and

(g) drying the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, an alternative method of making acrystalline form of the compound or derivative having formula (IIa), ora salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can includethe steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of methanol and water, so as to remove any undissolvedsolids;

(d) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water at −20° C. so as to produce an oily layer at thebottom of the volume of methanol and water;

(e) decanting the volume of methanol and water from the oily layer atthe bottom of the volume of methanol and water; and

(f) drying the oily layer at room temperature so as to crystallize thecrystalline form of the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, another alternative method of making acrystalline form of the compound or derivative having formula (IIa), ora salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can includethe steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofethanol and water in a 3:2 volume:volume ratio at room temperature,wherein the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, is added in an amountof about 200 milligrams per milliliter of the volume of ethanol andwater;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of ethanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of ethanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, in the volume ofethanol and water, to −10° C. for about 48 hours so as to produce thecrystalline form of the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(e) decanting the volume of ethanol and water from the crystalline formof the compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen, so as to isolate the crystallineform of the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

(f) drying the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In yet another embodiment, a method of making a compound or derivativehaving formula (IIa), or a salt, solvate, or prodrug thereof, wherein Y³is absent, can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen;

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with aphosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen, andthe phosphitylating reagent, with a (0<x≤20) molar equivalent amount ofa Brønsted acid or base;

(c) processing the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, the phosphitylatingreagent, and, optionally, the Brønsted acid or base so as to produce thecompound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is absent;

(d) adding, optionally, the compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen,optionally, the phosphitylating reagent, optionally, the Brønsted acidor base, and the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is absent, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

(e) isolating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is absent; and

optionally, (e1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is absent, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is absent, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is absent, canbe a polar organic solvent from among, for example, preferably, theClass 2 Residual Solvents listed in Table 2, or optionally, fornon-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S.PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (IIa), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen;

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with aphosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen, andthe phosphitylating reagent, with a (0<x≤20) molar equivalent amount ofa Brønsted acid or base;

(c) processing the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, the phosphitylatingreagent, and, optionally, the Brønsted acid or base so as to produce acompound or derivative having formula (IIa), or a salt, solvate, orprodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶ is hydrogen, optionally, the phosphitylating reagent,optionally, the Brønsted acid or base, and the compound or derivativehaving formula (IIa), or salt, solvate, or prodrug thereof, wherein Y³is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (Ia), or salt, solvate, or prodrug thereof,wherein R⁶ is hydrogen, optionally, the phosphitylating reagent,optionally, the Brønsted acid or base, and the compound or derivativehaving formula (IIa), or salt, solvate, or prodrug thereof, wherein Y³is absent, so as to produce the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (Ia), or salt, solvate, or prodrugthereof, wherein R⁶ is hydrogen, optionally, the phosphitylatingreagent, optionally, the Brønsted acid or base, optionally, the compoundor derivative having formula (IIa), or salt, solvate, or prodrugthereof, wherein Y³ is absent, and the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ issulfur, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (g1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, canbe a polar organic solvent from among, for example, preferably, theClass 2 Residual Solvents listed in Table 2, or optionally, fornon-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S.PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (IIa), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen;

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with athiophosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen, andthe thiophosphorylating reagent, with a (0<x≤20) molar equivalent amountof a Brønsted acid or base;

(c) processing the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, thethiophosphorylating reagent, and, optionally, the Brønsted acid or base,so as to produce the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is sulfur;

(d) adding, optionally, the compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen,optionally, the thiophosphorylating reagent, optionally, the Brønstedacid or base, and the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is sulfur, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (Ia), or salt, solvate, or prodrug thereof, wherein R⁶ ishydrogen;

(e) isolating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (e1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, canbe a polar organic solvent from among, for example, preferably, theClass 2 Residual Solvents listed in Table 2, or optionally, fornon-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S.PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (IIa), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (Ia-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphorylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted acid or base;

(c) processing the compound or derivative having formula (Ia-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphorylating reagent, and, optionally, the Brønstedacid or base, so as to produce the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(d) adding, optionally, the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, optionally, the phosphorylating reagent, optionally, theBrønsted acid or base, and the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, toiced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen;

(e) isolating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (e1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, canbe a polar organic solvent from among, for example, preferably, theClass 2 Residual Solvents listed in Table 2, or optionally, fornon-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S.PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (IIa), or a salt, solvate, orprodrug thereof, wherein Y³ is oxygen, can include the steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of methanol and water, so as to remove any undissolvedsolids;

(d) adding a volume of acetone to the solution of the compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, in the volume of methanol and water, wherein thevolume of acetone is about 2 to about 5 times the combined volume ofmethanol and water;

(e) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, the volume ofacetone, and the volume of methanol and water at −20° C. so as toprecipitate the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen;

(f) filtering the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, the volume of acetone, and the volume of methanol and water soas to isolate the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen; and

(g) drying the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, an alternative method of making acrystalline form of the compound or derivative having formula (IIa), ora salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can includethe steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of methanol and water, so as to remove any undissolvedsolids;

(d) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water at −20° C. so as to produce an oily layer at thebottom of the volume of methanol and water;

(e) decanting the volume of methanol and water from the oily layer atthe bottom of the volume of methanol and water; and

(f) drying the oily layer at room temperature so as to crystallize thecrystalline form of the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, another alternative method of making acrystalline form of the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen, can include thesteps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofethanol and water in a 3:2 volume:volume ratio at room temperature,wherein the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, is added in an amountof about 200 milligrams per milliliter of the volume of ethanol andwater;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of ethanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of ethanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, in the volume ofethanol and water, to −10° C. for about 48 hours so as to produce thecrystalline form of the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(e) decanting the volume of ethanol and water from the crystalline formof the compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen, so as to isolate the crystallineform of the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

(f) drying the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In yet another embodiment, a method of making a compound or derivativehaving formula (IIa), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (Ia-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphitylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted acid or base;

(c) processing the compound or derivative having formula (Ia-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphitylating reagent, and, optionally, the Brønstedacid or base so as to produce a compound or derivative having formula(IIa), or a salt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted acid or base, and thecompound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted acid or base, and thecompound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is absent, so as to produce the compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (Ia-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally,the phosphitylating reagent, optionally, the Brønsted acid or base,optionally, the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is absent, and the compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (g1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, canbe a polar organic solvent from among, for example, preferably, theClass 2 Residual Solvents listed in Table 2, or optionally, fornon-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S.PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In a particular embodiment, a method of making a crystalline form of thecompound or derivative having formula (IIa), or a salt, solvate, orprodrug thereof, wherein Y³ is oxygen, can include the steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of methanol and water, so as to remove any undissolvedsolids;

(d) adding a volume of acetone to the solution of the compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, in the volume of methanol and water, wherein thevolume of acetone is about 2 to about 5 times the combined volume ofmethanol and water;

(e) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, the volume ofacetone, and the volume of methanol and water at −20° C. so as toprecipitate the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen;

(f) filtering the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, the volume of acetone, and the volume of methanol and water soas to isolate the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen; and

(g) drying the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, an alternative method of making acrystalline form of the compound or derivative having formula (IIa), ora salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can includethe steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofmethanol and water in a 3:2 volume:volume ratio at room temperature;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of methanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of methanol and water, so as to remove any undissolvedsolids;

(d) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofmethanol and water at −20° C. so as to produce an oily layer at thebottom of the volume of methanol and water;

(e) decanting the volume of methanol and water from the oily layer atthe bottom of the volume of methanol and water; and

(f) drying the oily layer at room temperature so as to crystallize thecrystalline form of the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In a particular embodiment, another alternative method of making acrystalline form of the compound or derivative having formula (IIa), ora salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can includethe steps of:

(a) adding the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, to a volume ofethanol and water in a 3:2 volume:volume ratio at room temperature,wherein the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, is added in an amountof about 200 milligrams per milliliter of the volume of ethanol andwater;

(b) stirring the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, and the volume ofethanol and water so as to dissolve the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, in the volume of ethanol and water;

(c) filtering the solution of the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, inthe volume of ethanol and water, so as to remove any undissolved solids;

(d) cooling the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, in the volume ofethanol and water, to −10° C. for about 48 hours so as to produce thecrystalline form of the compound or derivative having formula (IIa), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(e) decanting the volume of ethanol and water from the crystalline formof the compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen, so as to isolate the crystallineform of the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

(f) drying the crystalline form of the compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, at room temperature.

The process described herein effects a preparation of a crystalline formof a compound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen.

In yet another embodiment, a method of making a compound or derivativehaving formula (IIa), or a salt, solvate, or prodrug thereof, wherein Y³is absent, can include the steps of:

(a) providing a compound or derivative having formula (Ia-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphitylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted acid or base;

(c) processing the compound or derivative having formula (Ia-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphitylating reagent, and, optionally, the Brønstedacid or base so as to produce the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding, optionally, the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, optionally, the phosphitylating reagent, optionally, theBrønsted acid or base, and the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is absent, toiced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

(e) isolating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is absent; and

optionally, (e1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is absent, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is absent, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is absent, canbe a polar organic solvent from among, for example, preferably, theClass 2 Residual Solvents listed in Table 2, or optionally, fornon-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S.PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (IIa), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (Ia-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphitylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted acid or base;

(c) processing the compound or derivative having formula (Ia-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphitylating reagent, and, optionally, the Brønstedacid or base so as to produce a compound or derivative having formula(IIa), or a salt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (Ia-H), wherein R⁶, R⁷, and R⁸ are eachhydrogen, optionally, the phosphitylating reagent, optionally, theBrønsted acid or base, and the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (Ia-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted acid or base, and thecompound or derivative having formula (IIa), or salt, solvate, orprodrug thereof, wherein Y³ is absent, so as to produce the compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (Ia-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally,the phosphitylating reagent, optionally, the Brønsted acid or base,optionally, the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is absent, and the compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (g1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, canbe a polar organic solvent from among, for example, preferably, theClass 2 Residual Solvents listed in Table 2, or optionally, fornon-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S.PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (IIa), or salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (Ia-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (Ia-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a thiophosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the thiophosphorylating reagent, with a (0<x≤20)molar equivalent amount of a Brønsted acid or base;

(c) processing the compound or derivative having formula (Ia-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the thiophosphorylating reagent, and, optionally, the Brønstedacid or base, so as to produce the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur;

(d) adding, optionally, the compound or derivative having formula(Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, optionally, the thiophosphorylating reagent, optionally,the Brønsted acid or base, and the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, toiced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (Ia-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen;

(e) isolating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (e1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of compound orderivative having formula (IIa), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, canbe a polar organic solvent from among, for example, preferably, theClass 2 Residual Solvents listed in Table 2, or optionally, fornon-human use, the Class 3 Residual Solvents listed in Table 3 in THENATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S.PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In an embodiment, a method of making a compound or derivative havingformula (III), or a salt, solvate, or prodrug thereof, can include thesteps of:

(a) providing a compound or derivative having formula (II), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (1<x≤10) molar equivalent amountof a carbodiimide reagent, in the presence of water or an organicsolvent co-reagent in an amount of up to 10 molar equivalents;

optionally, (b1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, the compound or derivativehaving formula (3), or salt thereof, the carbodiimide reagent, and thewater or organic solvent co-reagent, with at least a catalytic amount ofa divalent metal salt;

(c) processing the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the carbodiimide reagent, the water or organicsolvent co-reagent, and, optionally, the divalent metal salt, so as toproduce the compound or derivative having formula (III), or salt,solvate, or prodrug thereof;

(d) adding, optionally, the compound or derivative having formula (II),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, thecarbodiimide reagent, the water or organic solvent co-reagent,optionally, the divalent metal salt, and the compound or derivativehaving formula (III), or salt, solvate, or prodrug thereof, to icedwater;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (II), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (III), or salt,solvate, or prodrug thereof; and

optionally, (e1) treating the compound or derivative having formula(III), or salt, solvate, or prodrug thereof, with deprotectionreagent(s) in a polar organic solvent co-reagent so as to remove anyprotecting groups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (III), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (III), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In another embodiment, a method of making a compound or derivativehaving formula (III), or a salt, solvate, or prodrug thereof, caninclude the steps of:

(a) providing a compound or derivative having formula (II), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (0<x≤20) molar equivalent amountof an amine, in the presence of water or an organic solvent co-reagentin an amount of up to 10 molar equivalents;

optionally, (b1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, the compound or derivativehaving formula (3), or salt thereof, the amine, and the water or organicsolvent co-reagent, with at least a catalytic amount of a divalent metalsalt;

(c) processing the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the amine, the water or organic solventco-reagent, and, optionally, the divalent metal salt, so as to producethe compound or derivative having formula (III), or salt, solvate, orprodrug thereof;

(d) adding, optionally, the compound or derivative having formula (II),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, the amine,the water or organic solvent co-reagent, optionally, the divalent metalsalt, and the compound or derivative having formula (III), or salt,solvate, or prodrug thereof, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (II), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (III), or salt,solvate, or prodrug thereof; and

optionally, (e1) treating the compound or derivative having formula(III), or salt, solvate, or prodrug thereof, with deprotectionreagent(s) in a polar organic solvent co-reagent so as to remove anyprotecting groups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (III), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (III), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (III), or a salt, solvate, or prodrug thereof, caninclude the steps of:

(a) providing a compound or derivative having formula (II), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (0<x≤10) molar equivalent amountof a Brønsted acid, in the presence of water or an organic solventco-reagent;

optionally, (b1) treating the compound or derivative having formula(II), or salt, solvate, or prodrug thereof, the compound or derivativehaving formula (3), or salt thereof, the Brønsted acid, and the water ororganic solvent co-reagent, with at least a catalytic amount of adivalent metal salt;

(c) processing the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the Brønsted acid, the water or organic solventco-reagent, and, optionally, the divalent metal salt, so as to producethe compound or derivative having formula (III), or salt, solvate, orprodrug thereof;

(d) adding, optionally, the compound or derivative having formula (II),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, the Brønstedacid, the water or organic solvent co-reagent, optionally, the divalentmetal salt, and the compound or derivative having formula (III), orsalt, solvate, or prodrug thereof, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (II), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (III), or salt,solvate, or prodrug thereof; and

optionally, (e1) treating the compound or derivative having formula(III), or salt, solvate, or prodrug thereof, with deprotectionreagent(s) in a polar organic solvent co-reagent so as to remove anyprotecting groups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (III), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (III), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In an embodiment, a method of making a compound or derivative havingformula (IIIa), or a salt, solvate, or prodrug thereof, can include thesteps of:

(a) providing a compound or derivative having formula (IIa), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (1<x≤10) molar equivalent amountof a carbodiimide reagent, in the presence of water or an organicsolvent co-reagent;

optionally, (b1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, the compound or derivativehaving formula (3), or salt thereof, the carbodiimide reagent, and thewater or organic solvent co-reagent, with at least a catalytic amount ofa divalent metal salt;

(c) processing the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the carbodiimide reagent, the water or organicsolvent co-reagent, and, optionally, the divalent metal salt, so as toproduce the compound or derivative having formula (IIIa), or salt,solvate, or prodrug thereof;

(d) adding, optionally, the compound or derivative having formula (IIa),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, thecarbodiimide reagent, the water or organic solvent co-reagent,optionally, the divalent metal salt, and the compound or derivativehaving formula (IIIa), or salt, solvate, or prodrug thereof, to icedwater;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (IIIa), or salt,solvate, or prodrug thereof;

optionally, (e1) treating the compound or derivative having formula(IIIa), or salt, solvate, or prodrug thereof, with deprotectionreagent(s) in a polar organic solvent co-reagent so as to remove anyprotecting groups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIIa), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (IIIa), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In another embodiment, a method of making a compound or derivativehaving formula (IIIa), or a salt, solvate, or prodrug thereof, caninclude the steps of:

(a) providing a compound or derivative having formula (IIa), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (0<x≤10 molar equivalent amount ofan amine, in the presence of a water or an organic solvent co-reagent inan amount of up to 10 molar equivalents;

optionally, (b1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, the compound or derivativehaving formula (3), or salt thereof, the amine, and the water or anorganic solvent co-reagent, with at least a catalytic amount of adivalent metal salt;

(c) processing the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the amine, the water or organic solventco-reagent, and, optionally, the divalent metal salt, so as to producethe compound or derivative having formula (IIIa), or salt, solvate, orprodrug thereof;

(d) adding, optionally, the compound or derivative having formula (IIa),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, the amine,the water or organic solvent co-reagent, optionally, the divalent metalsalt, and the compound or derivative having formula (IIIa), or salt,solvate, or prodrug thereof, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (IIIa), or salt,solvate, or prodrug thereof; and

optionally, (e1) treating the compound or derivative having formula(IIIa), or salt, solvate, or prodrug thereof, with deprotectionreagent(s) in a polar organic solvent co-reagent so as to remove anyprotecting groups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIIa), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (IIIa), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (IIIa), or a salt, solvate, or prodrug thereof, caninclude the steps of:

(a) providing a compound or derivative having formula (IIa), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative heaving formula (IIa), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (0<x≤10) molar equivalent amountof a Brønsted acid, in the presence of water or an organic solventco-reagent in an amount of up to 10 molar equivalents;

optionally, (b1) treating the compound or derivative having formula(IIa), or salt, solvate, or prodrug thereof, the compound or derivativehaving formula (3), or salt thereof, the Brønsted acid, and the water ororganic solvent co-reagent, with at least a catalytic amount of adivalent metal salt;

(c) processing the compound or derivative having formula (IIa), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the Brønsted acid, the water or organic solventco-reagent, and, optionally, the divalent metal salt, so as to producethe compound or derivative having formula (IIIa), or salt, solvate, orprodrug thereof;

(d) adding, optionally, the compound or derivative having formula (IIa),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, the Brønstedacid, the water or organic solvent co-reagent, optionally, the divalentmetal salt, and the compound or derivative having formula (IIIa), orsalt, solvate, or prodrug thereof, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IIa), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(h) isolating the compound or derivative having formula (IIIa), or salt,solvate, or prodrug thereof; and

optionally, (h1) treating the compound or derivative having formula(IIIa), or salt, solvate, or prodrug thereof, with deprotectionreagent(s) in a polar organic solvent co-reagent so as to remove anyprotecting groups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (IIIa), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (IIIa), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In an embodiment, a method of making a compound or derivative havingformula (IV), or a salt, solvate, or prodrug thereof, can include thesteps of:

(a) providing a compound or derivative having formula (I), or salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, with a (1<x<10) molar equivalent amount ofa concentrated basic aqueous solution of reducing agent reagent, in thepresence of a (5<x<50) molar equivalent amount of an organic solventco-reagent;

(c) processing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, the concentrated aqueous solution ofreducing agent reagent, and the organic solvent co-reagent so as toproduce the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof;

(d) adding, optionally, the compound or derivative having formula (I),or salt, solvate, or prodrug thereof, optionally, the concentratedaqueous solution of reducing agent reagent, the organic solventco-reagent, and the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, to water;

(e) extracting, optionally, the compound or derivative having formula(I), or salt, solvate, or prodrug thereof, optionally, the concentratedaqueous solution of reducing agent reagent, the organic solventco-reagent, the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, and water with organic solvent; and

(f) isolating the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IV), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (IV),or salt, solvate, or prodrug thereof, can be a polar organic solventfrom among, for example, preferably, the Class 2 Residual Solventslisted in Table 2, or optionally, for non-human use, the Class 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In another embodiment, a method of making a compound or derivativehaving formula (IV), or a salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl, caninclude the steps of:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl;

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with a molar equivalent amount ofa reducing agent reagent, in the presence of a (1<x<10) molar equivalentamount of an organic solvent co-reagent;

(c) processing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, the reducing agent reagent, andthe organic solvent co-reagent so as to produce the compound orderivative having formula (IV), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl;

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted compound or derivativehaving formula (I), or salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl; and

(d) isolating the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IV), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (IV),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each—C(O)R′, and wherein R′ is methyl or —C₁alkyl, can be a polar organicsolvent from among, for example, preferably, the Class 2 ResidualSolvents listed in Table 2, or optionally, for non-human use, the Class3 Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In an embodiment, a method of making a compound or derivative havingformula (IVa), or a salt, solvate, or prodrug thereof, can include thesteps of:

(a) providing a compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, with a (1<x<10) molar equivalent amount ofa concentrated basic aqueous solution of reducing agent reagent, in thepresence of a (5<x<50) molar equivalent amount of an organic solventco-reagent;

(c) processing the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, the concentrated aqueous solution ofreducing agent reagent, and the organic solvent co-reagent so as toproduce the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof;

(d) adding, optionally, the compound or derivative having formula (Ia),or salt, solvate, or prodrug thereof, optionally, the concentratedaqueous solution of reducing agent reagent, the organic solventco-reagent, and the compound or derivative having formula (IVa), orsalt, solvate, or prodrug thereof, to water;

(e) extracting, optionally, the compound or derivative having formula(Ia), or salt, solvate, or prodrug thereof, optionally, the concentratedaqueous solution of reducing agent reagent, the organic solventco-reagent, the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, and water with organic solvent; and

(f) isolating the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IVa), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IVa), or salt, solvate, or prodrug thereof, can be a polar organicsolvent from among, for example, preferably, the Class 2 ResidualSolvents listed in Table 2, or optionally, for non-human use, the Class3 Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In another embodiment, a method of making a compound or derivativehaving formula (IVa), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl,can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl;

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with a molar equivalent amount ofa reducing agent reagent, in the presence of a (1<x<10) molar equivalentamount of an organic solvent co-reagent;

(c) processing the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, the reducing agent reagent, andthe organic solvent co-reagent so as to produce the compound orderivative having formula (IVa), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl;

optionally, (c1) removing by-products resulting from the processing stepunder reduced pressure and temperature-controlled conditions;

optionally, (c2) separately isolating unreacted compound or derivativehaving formula (Ia), or salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or —C₁alkyl; and

(d) isolating the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IVa), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IVa), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸, areeach —C(O)R′, and wherein R′ is methyl or —C₁alkyl, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In an embodiment, a method of making a compound or derivative havingformula (IV-H), or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (IV), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, with a molar (x≤10) equivalent amount of analcohol (e.g., methanol, or ethanol) and at least a catalytic amount ofa Brønsted inorganic base;

(c) processing the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, the alcohol, and the Brønsted inorganicbase so as to produce the compound or derivative having formula (IV-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

optionally, (c1) evaporating any volatile by-products resulting from theprocessing step;

(d) isolating the compound or derivative having formula (IV-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (d1) separately isolating the unreacted compound orderivative having formula (IV), or salt, solvate, or prodrug thereof;and

optionally, (d2) drying the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IV-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In another embodiment, a method of making a compound or derivativehaving formula (IV-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (IV), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl;

(b) treating the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with a molar (x≤10) equivalentamount of an alcohol (e.g., methanol, or ethanol) and a catalytic amountof a Brønsted inorganic base;

(c) processing the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, the alcohol, and the Brønstedinorganic base so as to produce the compound or derivative havingformula (IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen;

optionally, (c1) evaporating any volatile by-products resulting from theprocessing step;

(d) isolating the compound or derivative having formula (IV-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (d1) separately isolating the unreacted compound orderivative having formula (IV), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl; and

optionally, (d2) drying the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IV-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (IV-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, with a (1<x<10) molar equivalent amount ofa concentrated basic aqueous solution of reducing agent reagent, in thepresence of a (5<x<50) molar equivalent amount of a polar organicsolvent co-reagent;

(c) processing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, the concentrated aqueous solution ofreducing agent reagent, and the polar organic solvent co-reagent so asto produce a compound or derivative having formula (IV), or a salt,solvate, or prodrug thereof, while continuously extracting in situ thecompound or derivative having formula (IV), or salt, solvate, or prodrugthereof, into organic solvent;

optionally, (c1) removing by-products resulting from processing step (c)by continuously extracting with water;

(d) separating the organic solvent phase, in which the compound orderivative having formula (IV), or salt, solvate, or prodrug thereof, isdissolved, from the aqueous phase;

optionally, (d1) removing the organic solvent under reduced pressure andtemperature-controlled conditions so as to provide a viscous pastecontaining the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof;

(e) treating the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, and residual organic solvent, with a molar(x≤10) equivalent amount of an alcohol (e.g., methanol, or ethanol) andat least a catalytic amount of a Brønsted inorganic base;

(f) processing the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, residual organic solvent, the alcohol, andthe Brønsted inorganic base so as to produce the compound or derivativehaving formula (IV-H), or salt, solvate, or prodrug thereof, wherein R⁶,R⁷, and R⁸ are each hydrogen;

optionally, (f1) evaporating any volatile by-products resulting fromprocessing step (f);

(g) isolating the compound or derivative having formula (IV-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (g1) separately isolating the unreacted compound orderivative having formula (IV), or salt, solvate, or prodrug thereof;and

optionally, (g2) drying the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of the groupconsisting of liquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IV-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (IV-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl;

(b) treating the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with a (1<x<10) molar equivalentamount of a concentrated basic aqueous solution of reducing agentreagent, in the presence of a (5<x<50) molar equivalent amount of apolar organic solvent co-reagent;

(c) processing the compound or derivative having formula (I), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, the concentrated aqueous solutionof reducing agent reagent, and the polar organic solvent co-reagent soas to produce a compound or derivative having formula (IV), or a salt,solvate or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′, andwherein R′ is methyl or —C₁alkyl, while continuously extracting in situthe compound or derivative having formula (IV), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′is methyl or —C₁alkyl, into organic solvent;

optionally, (c1) removing by-products resulting from processing step (c)by continuously extracting with water;

(d) separating the organic solvent phase, in which the compound orderivative having formula (IV), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, is dissolved, from the aqueous phase;

optionally, (d1) removing the organic solvent under reduced pressure andtemperature-controlled conditions so as to provide a viscous pastecontaining the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl;

(e) treating the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, and residual organic solvent, witha molar (x≤10) equivalent amount of an alcohol (e.g., methanol, orethanol) and at least a catalytic amount of a Brønsted inorganic base;

(f) processing the compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, residual organic solvent, thealcohol, and the Brønsted inorganic base so as to produce the compoundor derivative having formula (IV-H), or salt, solvate, or prodrugthereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (f1) evaporating any volatile by-products resulting fromprocessing step (f);

(g) isolating the compound or derivative having formula (IV-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

optionally, (g1) separately isolating the unreacted compound orderivative having formula (IV), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl; and

optionally, (g2) drying the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IV-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, can be a polar organic solvent from among, for example,preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In an embodiment, a method of making a compound or derivative havingformula (IVa-H), or a salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (IVa), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, with a molar (x≤10) equivalent amount of analcohol (e.g., methanol, or ethanol) and at least a catalytic amount ofa Brønsted inorganic base;

(c) processing the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, the alcohol, and the Brønsted inorganicbase so as to produce the compound or derivative having formula (IVa-H),or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

optionally, (c1) evaporating any volatile by-products resulting from theprocessing step;

(d) isolating the compound or derivative having formula (IVa-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

optionally, (d1) separately isolating the unreacted compound orderivative having formula (IVa), or salt, solvate, or prodrug thereof;and

optionally, (d2) drying the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IVa-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In another embodiment, a method of making a compound or derivativehaving formula (IVa-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (IVa), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl;

(b) treating the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with a molar (x≤10) equivalentamount of an alcohol (e.g., methanol, or ethanol) and a catalytic amountof a Brønsted inorganic base;

(c) processing the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, the alcohol, and the Brønstedinorganic base so as to produce the compound or derivative havingformula (IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen;

optionally, (c1) evaporating any volatile by-products resulting from theprocessing step;

(d) isolating the compound or derivative having formula (IVa-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

optionally, (d1) separately isolating the unreacted compound orderivative having formula (IVa), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl; and

optionally, (d2) drying the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IVa-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (IVa-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, with a (1<x<10) molar equivalent amount ofa concentrated basic aqueous solution of reducing agent reagent, in thepresence of a (5<x<50) molar equivalent amount of a polar organicsolvent co-reagent;

(c) processing the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, the concentrated aqueous solution ofreducing agent reagent, and polar organic solvent co-reagent so as toproduce a compound or derivative having formula (IVa), or a salt,solvate, or prodrug thereof, while continuously extracting in situ thecompound or derivative having formula (IVa), or salt, solvate, orprodrug thereof, into organic solvent;

optionally, (c1) removing by-products resulting from processing step (c)by continuously extracting the organic solvent with water;

(d) separating the organic solvent phase, in which the compound orderivative having formula (IVa), or salt, solvate, or prodrug thereof,is dissolved, from the aqueous phase;

optionally, (d1) removing the organic solvent under reduced pressure andtemperature-controlled conditions so as to provide a viscous pastecontaining the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof;

(e) treating the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, and residual organic solvent, with a molar(x≤10) equivalent amount of an alcohol (e.g., methanol, or ethanol) andat least a catalytic amount of a Brønsted inorganic base;

(f) processing the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, residual organic solvent, the alcohol, andthe Brønsted inorganic base so as to produce the compound or derivativehaving formula (IVa-H), or salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen;

optionally, (f1) evaporating any volatile by-products resulting fromprocessing step (f);

(g) isolating the compound or derivative having formula (IVa-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

optionally, (g1) separately isolating the unreacted compound orderivative having formula (IVa), or salt, solvate, or prodrug thereof;and

optionally, (g2) drying the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (IVa-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (IVa-H), or a salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen, can include the steps of:

(a) providing a compound or derivative having formula (Ia), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl;

(b) treating the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, with a (1<x<10) molar equivalentamount of a concentrated basic aqueous solution of reducing agentreagent, in the presence of a (5<x<50) molar equivalent amount of apolar organic solvent co-reagent;

(c) processing the compound or derivative having formula (Ia), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, the concentrated aqueous solutionof reducing agent reagent, and the polar organic solvent co-reagent soas to produce a compound or derivative having formula (IVa), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, while continuously extracting insitu the compound or derivative having formula (IVa), or salt, solvate,or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and whereinR′ is methyl or —C₁alkyl, into organic solvent;

optionally, (c1) removing by-products resulting from processing step (c)by continuously extracting the organic solvent with water;

(d) separating the organic solvent phase, in which the compound orderivative having formula (IVa), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl, is dissolved, from the aqueous phase;

optionally, (d1) removing the organic solvent under reduced pressure andtemperature-controlled conditions so as to provide a viscous pastecontaining the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl;

(e) treating the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, and residual organic solvent, witha molar (x≤10) equivalent amount of an alcohol (e.g., methanol, orethanol) and a catalytic amount of a Brønsted inorganic base;

(f) processing the compound or derivative having formula (IVa), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each —C(O)R′,and wherein R′ is methyl or —C₁alkyl, residual organic solvent, alcohol,and Brønsted inorganic base so as to produce the compound or derivativehaving formula (IVa-H), or salt, solvate, or prodrug thereof, whereinR⁶, R⁷, and R⁸ are each hydrogen;

optionally, (f1) evaporating any volatile by-products resulting fromprocessing step (f);

(g) isolating the compound or derivative having formula (IVa-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

optionally, (g1) separately isolating the unreacted compound orderivative having formula (IVa), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each —C(O)R′, and wherein R′ is methyl or—C₁alkyl; and

optionally, (g2) drying the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted mixing, milling, grinding, and extruding.Liquid-assisted mixing may be performed between about 5 Hz and about 50Hz for about 1 min to about 500 min, preferably between about 10 Hz andabout 40 Hz for about 15 min to about 180 min, and most preferablybetween about 20 Hz and about 30 Hz for about 60 min to about 120 min.Grinding may be performed between about 50 RPM and about 200 RPM,preferably between about 75 RPM and about 150 RPM, and most preferablybetween about 100 RPM and about 130 RPM.

In an embodiment, a method of making a compound or derivative havingformula (V), or a salt, solvate, or prodrug thereof, wherein Y³ isoxygen, can include the steps of:

(a) providing a compound or derivative having formula (IVb), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVb), or salt,solvate, or prodrug thereof, with a phosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVb), or salt, solvate, or prodrug thereof, and the phosphorylatingreagent, with a (0<x≤20) molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVb), or salt,solvate, or prodrug thereof, the phosphorylating reagent, and,optionally, the Brønsted base, so as to produce the compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen;

(d) adding, optionally, the compound or derivative having formula (IVb),or salt, solvate, or prodrug thereof, optionally, the phosphorylatingreagent, optionally, the Brønsted base, and the compound or derivativehaving formula (V), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IVb), or salt, solvate, or prodrug thereof;

(e) isolating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen;

optionally, (e1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹ and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between 50 RPM and about 200 RPM, preferably between about 75RPM and about 150 RPM, and most preferably between about 100 RPM andabout 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In another embodiment, a method of making a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (IVb), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVb), or salt,solvate, or prodrug thereof, with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVb), or salt, solvate, or prodrug thereof, and the phosphitylatingreagent, with a (0<x≤20) molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVb), or salt,solvate, or prodrug thereof, the phosphitylating reagent, and,optionally, the Brønsted base so as to produce a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (IVb), or salt, solvate, or prodrug thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,and the compound or derivative having formula (V), or salt, solvate, orprodrug thereof, wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (IVb), or salt, solvate, or prodrug thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,and the compound or derivative having formula (V), or salt, solvate, orprodrug thereof, wherein Y³ is absent, so as to produce the compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen;

(f) adding, optionally, the oxidizing agent reagent, the compound orderivative having formula (IVb), or salt, solvate, or prodrug thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,optionally, the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is absent, and the compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (g1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is absent, can include the steps of:

(a) providing a compound or derivative having formula (IVb), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVb), or salt,solvate, or prodrug thereof, with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVb), or salt, solvate, or prodrug thereof, and the phosphitylatingreagent, with a (0<x≤20) molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVb), or salt,solvate, or prodrug thereof, the phosphitylating reagent, and,optionally, the Brønsted base so as to produce the compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is absent;

(d) adding, optionally, the compound or derivative having formula (IVb),or salt, solvate, or prodrug thereof, optionally, the phosphitylatingreagent, optionally, the Brønsted base, and the compound or derivativehaving formula (V), or salt, solvate, or prodrug thereof, wherein Y³ isabsent, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IVb), or salt, solvate, or prodrug thereof;

(e) isolating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is absent; and

optionally, (e1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is absent, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is absent, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is absent, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (IVb), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVb), or salt,solvate, or prodrug thereof, with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVb), or salt, solvate, or prodrug thereof, and the phosphitylatingreagent, with a (0<x≤20) molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVb), or salt,solvate, or prodrug thereof, the phosphitylating reagent, and,optionally, the Brønsted base so as to produce a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (IVb), or salt, solvate, or prodrug thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,and the compound or derivative having formula (V), or salt, solvate, orprodrug thereof, wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (IVb), or salt, solvate, or prodrug thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,and the compound or derivative having formula (V), or salt, solvate, orprodrug thereof, wherein Y³ is absent, so as to produce the compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (IVb), or salt, solvate, orprodrug thereof, optionally, the phosphitylating reagent, optionally,the Brønsted base, optionally, the compound or derivative having formula(V), or salt, solvate, or prodrug thereof, wherein Y³ is absent, and thecompound or derivative having formula (V), or salt, solvate, or prodrugthereof, wherein Y³ is sulfur, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (g1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (IVb), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVb), or salt,solvate, or prodrug thereof, with a thiophosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVb), or salt, solvate, or prodrug thereof, and the thiophosphorylatingreagent, with a (0<x≤20) molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVb), or salt,solvate, or prodrug thereof, the thiophosphorylating reagent, and,optionally, the Brønsted base, so as to produce the compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur;

(d) adding, optionally, the compound or derivative having formula (IVb),or salt, solvate, or prodrug thereof, optionally, thethiophosphorylating reagent, optionally, the Brønsted base, and thecompound or derivative having formula (V), or salt, solvate, or prodrugthereof, wherein Y³ is sulfur, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IVb), or salt, solvate, or prodrug thereof;

(e) isolating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (e1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents, listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (IV-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (IV-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphorylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IV-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphorylating reagent, and optionally, the Brønstedbase, so as to produce the compound or derivative having formula (V), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(d) adding, optionally, the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, optionally, the phosphorylating reagent, optionally, theBrønsted base, and the compound or derivative having formula (V), orsalt, solvate, or prodrug thereof, wherein Y³ is oxygen, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen; and

(e) isolating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (e1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (IV-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (IV-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphitylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IV-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphitylating reagent, and, optionally, the Brønstedbase so as to produce a compound or derivative having formula (V), or asalt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (IV-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted base, and the compoundor derivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (IV-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted base, and the compoundor derivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is absent, so as to produce the compound or derivative havingformula (V), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (IV-H), or salt, solvate, orprodrug thereof, optionally, the phosphitylating reagent, optionally,the Brønsted base, optionally, the compound or derivative having formula(V), or salt, solvate, or prodrug thereof, wherein Y³ is absent, and thecompound or derivative having formula (V), or salt, solvate, or prodrugthereof, wherein Y³ is oxygen, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (g1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is absent, can include the steps of:

(a) providing a compound or derivative having formula (IV-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (IV-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphitylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IV-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphitylating reagent, and, optionally, the Brønstedbase so as to produce the compound or derivative having formula (V), orsalt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding, optionally, the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, optionally, the phosphitylating reagent, optionally, theBrønsted base, and the compound or derivative having formula (V), orsalt, solvate, or prodrug thereof, wherein Y³ is absent, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen;

(e) isolating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is absent; and

optionally, (e1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is absent, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is absent, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is absent, can be a polarorganic solvent from among, for example, preferably the Class 2 ResidualSolvents listed in Table 2, or optionally, for non-human use, the Class3 Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (IV-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (IV-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the phosphitylating reagent, with a (0<x≤20) molarequivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IV-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphitylating reagent, and, optionally, the Brønstedbase so as to produce a compound or derivative having formula (V), or asalt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (IV-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted base, and the compoundor derivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (IV-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted base, and the compoundor derivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is absent, so as to produce the compound or derivative havingformula (V), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (IV-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally,the phosphitylating reagent, optionally, the Brønsted base, optionally,the compound or derivative having formula (V), or salt, solvate, orprodrug thereof, wherein Y³ is absent, and the compound or derivativehaving formula (V), or salt, solvate, or prodrug thereof, wherein Y³ issulfur, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (g1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (V), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (IV-H), or a salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen;

(b) treating the compound or derivative having formula (IV-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a thiophosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, and the thiophosphorylating reagent, with a (0<x≤20)molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IV-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the thiophosphorylating reagent, and, optionally, the Brønstedbase, so as to produce the compound or derivative having formula (V), orsalt, solvate, or prodrug thereof, wherein Y³ is sulfur;

(d) adding, optionally, the compound or derivative having formula(IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ areeach hydrogen, optionally, the thiophosphorylating reagent, optionally,the Brønsted base, and the compound or derivative having formula (V), orsalt, solvate, or prodrug thereof, wherein Y³ is sulfur, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IV-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen;

(e) isolating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (e1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (V), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (V),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In an embodiment, a method of making a compound or derivative havingformula (Va), or a salt, solvate, or prodrug thereof, wherein Y³ isoxygen, can include the steps of:

(a) providing a compound or derivative having formula (IVc), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVc), or salt,solvate, or prodrug thereof, with a phosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVc), or salt, solvate, or prodrug thereof, and the phosphorylatingreagent, with a (0<x≤20) molar equivalent of a Brønsted base;

(c) processing the compound or derivative having formula (IVc), or salt,solvate, or prodrug thereof, the phosphorylating reagent, andoptionally, the Brønsted base, so as to produce the compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen;

(d) adding, optionally, the compound or derivative having formula (IVc),or salt, solvate, or prodrug thereof, optionally, the phosphorylatingreagent, optionally, the Brønsted base, and the compound or derivativehaving formula (Va), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IVc), or salt, solvate, or prodrug thereof;

(e) isolating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (e1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (Va), or salt, solvate,or prodrug thereof, wherein Y³ is oxygen, can be a polar organic solventfrom among, for example, preferably, the Class 2 Residual Solventslisted in Table 2, or optionally, for non-human use, the Class 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In another embodiment, a method of making a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (IVc), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVc), or salt,solvate, or prodrug thereof, with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVc), or salt, solvate, or prodrug thereof, and the phosphitylatingreagent, with a (0<x≤20) molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVc), or salt,solvate, or prodrug thereof, the phosphitylating reagent, and,optionally, the Brønsted base so as to produce a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (IVc), or salt, solvate, or prodrug thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,and the compound or derivative having formula (Va), or salt, solvate, orprodrug thereof, wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (IVc), or salt, solvate, or prodrug thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,and the compound or derivative having formula (Va), or salt, solvate, orprodrug thereof, wherein Y³ is absent, so as to produce the compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (IVc), or salt, solvate, orprodrug thereof, optionally, the phosphitylating reagent, optionally,the Brønsted base, optionally, the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is absent, andthe compound or derivative having formula (Va), or salt, solvate, orprodrug thereof, wherein Y³ is oxygen, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (g1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents, listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is absent, can include the steps of:

(a) providing a compound or derivative having formula (IVc), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVc), or salt,solvate, or prodrug thereof, with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVc), or salt, solvate, or prodrug thereof, and the phosphitylatingreagent, with a (0<x≤20) molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVc), or salt,solvate, or prodrug thereof, the phosphitylating reagent, and,optionally, the Brønsted base so as to produce the compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is absent;

(d) adding, optionally, the compound or derivative having formula (IVc),or salt, solvate, or prodrug thereof, optionally, the phosphitylatingreagent, optionally, the Brønsted base, and the compound or derivativehaving formula (Va), or salt, solvate, or prodrug thereof, wherein Y³ isabsent, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IVc), or salt, solvate, or prodrug thereof;

(e) isolating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is absent; and

optionally, (e1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is absent, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is absent, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is absent, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (IVc), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVc), or salt,solvate, or prodrug thereof, with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVc), or salt, solvate, or prodrug thereof, and the phosphitylatingreagent, with a (0<x≤20) molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVc), or salt,solvate, or prodrug thereof, the phosphitylating reagent, and,optionally, the Brønsted base so as to produce a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (IVc), or salt, solvate, or prodrug thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,and the compound or derivative having formula (Va), or salt, solvate, orprodrug thereof thereof, wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (IVc), or salt, solvate, or prodrug thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,and the compound or derivative having formula (Va), or salt, solvate, orprodrug thereof, wherein Y³ is absent, so as to produce the compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (IVc), or salt, solvate, orprodrug thereof, optionally, the phosphitylating reagent, optionally,the Brønsted base, optionally, the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is absent, andthe compound or derivative having formula (Va), or salt, solvate, orprodrug thereof, wherein Y³ is sulfur, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (g1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is absent, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (IVc), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (IVc), or salt,solvate, or prodrug thereof, with a thiophosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVc), or salt, solvate, or prodrug thereof, and the thiophosphorylatingreagent, with a (0<x≤20) molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVc), or salt,solvate, or prodrug thereof, the thiophosphorylating reagent, and,optionally, the Brønsted base, so as to produce the compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur;

(d) adding, optionally, the compound or derivative having formula (IVc),or salt, solvate, or prodrug thereof, optionally, thethiophosphorylating reagent, optionally, the Brønsted base, and thecompound or derivative having formula (Va), or salt, solvate, or prodrugthereof, wherein Y³ is sulfur, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IVc), or salt, solvate, or prodrug thereof;

(e) isolating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (e1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (Va),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (IVa-H), or asalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

(b) treating the compound or derivative having formula (IVa-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, and the phosphorylating reagent, with a (0<x≤20)molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVa-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphorylating reagent, and, optionally, the Brønstedbase, so as to produce the compound or derivative having formula (Va),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen;

(d) adding, optionally, the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, optionally, the phosphorylating reagent, optionally,the Brønsted base, and the compound or derivative having formula (Va),or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, to icedwater;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen;

(e) isolating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (e1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (Va), or salt, solvate,or prodrug thereof, wherein Y³ is oxygen, can be a polar organic solventfrom among, for example, preferably, the Class 2 Residual Solventslisted in Table 2, or optionally, for non-human use, the Class 3Residual Solvents listed in Table 3 in THE NATIONAL FORMULARY, UNITEDSTATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIAL CONVENTION 2006) (USP30 at <467>), incorporated by reference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is oxygen, can include the steps of:

(a) providing a compound or derivative having formula (IVa-H), or asalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

(b) treating the compound or derivative having formula (IVa-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, with a (0<x≤20) molar equivalent amount of a Brønstedbase;

(c) processing the compound or derivative having formula (IVa-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphitylating reagent, and, optionally, the Brønstedbase so as to produce a compound or derivative having formula (Va), or asalt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (IVa-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted base, and the compoundor derivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (IVa-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted base, and the compoundor derivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is absent, so as to produce the compound or derivative havingformula (Va), or salt, solvate, or prodrug thereof, wherein Y³ isoxygen;

(f) adding, optionally, the oxidizing agent reagent, the compound orderivative having formula (IVa-H), or salt, solvate, or prodrug thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,optionally, the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is absent, and the compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen; and

optionally, (g1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is oxygen, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is oxygen, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is oxygen, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is absent, can include the steps of:

(a) providing a compound or derivative having formula (IVa-H), or asalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

(b) treating the compound or derivative having formula (IVa-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, and the phosphitylating reagent, with a (0<x≤20)molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVa-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphitylating reagent, and, optionally, the Brønstedbase so as to produce the compound or derivative having formula (Va), orsalt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding, optionally, the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, optionally, the phosphitylating reagent, optionally,the Brønsted base, and the compound or derivative having formula (Va),or salt, solvate, or prodrug thereof, wherein Y³ is absent, to icedwater;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen;

(g) isolating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is absent; and

optionally, (g1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is absent, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is absent, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is absent, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (IVa-H), or asalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

(b) treating the compound or derivative having formula (IVa-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a phosphitylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, and the phosphitylating reagent, with a (0<x≤20)molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVa-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the phosphitylating reagent, and, optionally, the Brønstedbase so as to produce a compound or derivative having formula (Va), or asalt, solvate, or prodrug thereof, wherein Y³ is absent;

(d) adding an oxidizing agent reagent to, optionally, the compound orderivative having formula (IVa-H), or salt, solvate, or prodrug thereof,wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally, thephosphitylating reagent, optionally, the Brønsted base, and the compoundor derivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is absent;

(e) processing the oxidizing agent reagent, optionally, the compound orderivative having formula (IVa-H), or salt, solvate, or prodrug, whereinR⁶, R⁷, and R⁸ are each hydrogen, optionally, the phosphitylatingreagent, optionally, the Brønsted base, and the compound or derivativehaving formula (Va), or salt, solvate, or prodrug thereof, wherein Y³ isabsent, so as to produce the compound or derivative having formula (Va),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur;

(f) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (IVa-H), or salt, solvate, orprodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen, optionally,the phosphitylating reagent, optionally, the Brønsted base, optionally,the compound or derivative having formula (Va), or salt, solvate, orprodrug thereof, wherein Y³ is absent, and the compound or derivativehaving formula (Va), or salt, solvate, or prodrug thereof, wherein Y³ issulfur, to iced water;

optionally, (f1) adjusting the pH of the aqueous phase with an aqueousbase;

(g) isolating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (g1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent in the abovemethod of making a compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur, can be a polarorganic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (Va), or a salt, solvate, or prodrug thereof, wherein Y³is sulfur, can include the steps of:

(a) providing a compound or derivative having formula (IVa-H), or asalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen;

(b) treating the compound or derivative having formula (IVa-H), or salt,solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are each hydrogen,with a thiophosphorylating reagent;

optionally, (b1) treating the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, and the thiophosphorylating reagent, with a (0<x≤20)molar equivalent amount of a Brønsted base;

(c) processing the compound or derivative having formula (IVa-H), orsalt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸ are eachhydrogen, the thiophosphorylating reagent, and, optionally, the Brønstedbase, so as to produce the compound or derivative having formula (Va),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur;

(d) adding, optionally, the compound or derivative having formula(IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷, and R⁸are each hydrogen, optionally, the thiophosphorylating reagent,optionally, the Brønsted base, and the compound or derivative havingformula (Va), or salt, solvate, or prodrug thereof, wherein Y³ issulfur, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (IVa-H), or salt, solvate, or prodrug thereof, wherein R⁶, R⁷,and R⁸ are each hydrogen;

(e) isolating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, wherein Y³ is sulfur; and

optionally, (e1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, withdeprotection reagent(s) in a polar organic solvent co-reagent so as toremove any protecting groups of R⁷, R⁸, Y¹, and/or Y².

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting ofliquid-assisted grinding and extruding. Liquid-assisted grinding may beperformed between about 50 RPM and about 200 RPM, preferably betweenabout 75 RPM and about 150 RPM, and most preferably between about 100RPM and about 130 RPM.

The process described herein effects a preparation of a compound orderivative having formula (Va), or salt, solvate, or prodrug thereof,wherein Y³ is sulfur, under almost solventless conditions.

The polar organic solvent co-reagent and isolation solvent employed inthe above method of making a compound or derivative having formula (Va),or salt, solvate, or prodrug thereof, wherein Y³ is sulfur, can be apolar organic solvent from among, for example, preferably, the Class 2Residual Solvents listed in Table 2, or optionally, for non-human use,the Class 3 Residual Solvents listed in Table 3 in THE NATIONALFORMULARY, UNITED STATES PHARMACOPEIA 30 <467> (U.S. PHARMACOPEIALCONVENTION 2006) (USP 30 at <467>), incorporated by reference herein inits entirety.

In an embodiment, a method of making a compound or derivative havingformula (VI), or a salt, solvate, or prodrug thereof, can include thesteps of:

(a) providing a compound or derivative having formula (V), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (1<x≤10) molar equivalent amountof a carbodiimide reagent, in the presence of water or an organicsolvent co-reagent in an amount of up to 10 molar equivalents;

optionally, (b1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, the compound or derivative havingformula (3), or salt thereof, the carbodiimide reagent, and the water ororganic solvent co-reagent, with at least a catalytic amount of adivalent salt;

(c) processing the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the carbodiimide reagent, the water or organicsolvent co-reagent, and, optionally, the divalent metal salt, so as toproduce the compound or derivative having formula (VI), or salt,solvate, or prodrug thereof;

(d) adding, optionally, the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, thecarbodiimide reagent, the water or organic solvent co-reagent,optionally, the divalent metal salt, and the compound or derivativehaving formula (VI), or salt, solvate, or prodrug thereof, to icedwater;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (V), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (VI), or salt,solvate, or prodrug thereof; and

optionally, (e1) treating the compound or derivative having formula(VI), or salt, solvate, or prodrug thereof, with deprotection reagent(s)in a polar organic solvent co-reagent so as to remove any protectinggroups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (VI), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (VI), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In another embodiment, a method of making a compound or derivativehaving formula (VI), or a salt, solvate, or prodrug thereof, can includethe steps of:

(a) providing a compound or derivative having formula (V), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (0<x≤10) molar equivalent amountof an amine, in the presence of water or an organic solvent co-reagent,in an amount of up to 10 molar equivalents;

optionally, (b1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, the compound or derivative havingformula (3), or salt thereof, the amine, and the water or organicsolvent co-reagent, with at least a catalytic amount of a divalent metalsalt;

(c) processing the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the amine, the water or organic solventco-reagent, and, optionally, the divalent metal salt, so as to producethe compound or derivative having formula (VI), or salt, solvate, orprodrug thereof;

(d) adding, optionally, the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, the amine,the water or organic solvent co-reagent, optionally, the divalent metalsalt, and the compound or derivative having formula (VI), or salt,solvate, or prodrug thereof, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the compound or derivative having formula(V), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (VI), or salt,solvate, or prodrug thereof; and

optionally, (e1) treating the compound or derivative having formula(VI), or salt, solvate, or prodrug thereof, with deprotection reagent(s)in a polar organic solvent co-reagent so as to remove any protectinggroups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (VI), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (VI), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (VI), or a salt, solvate, or prodrug thereof, can includethe steps of:

(a) providing a compound or derivative having formula (V), or salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (0<x≤10) molar equivalent amountof a Brønsted acid, in the presence of water or an organic solventco-reagent, in an amount of up to 10 molar equivalents;

optionally, (b1) treating the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, the compound or derivative havingformula (3), or salt thereof, the Brønsted acid, and the water ororganic solvent co-reagent, with at least a catalytic amount of adivalent metal salt;

(c) processing the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the Brønsted acid, the water or organic solventco-reagent, and, optionally, the divalent metal salt, so as to producethe compound or derivative having formula (VI), or salt, solvate, orprodrug thereof;

(d) adding, optionally, the compound or derivative having formula (V),or salt, solvate, or prodrug thereof, the compound or derivative havingformula (3), or salt thereof, optionally, the Brønsted acid, the wateror organic solvent co-reagent, optionally, the divalent metal salt, andthe compound or derivative having formula (VI), or salt, solvate, orprodrug thereof, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (V), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (VI), or salt,solvate, or prodrug thereof; and

optionally, (e1) treating the compound or derivative having formula(VI), or salt, solvate, or prodrug thereof, with deprotection reagent(s)in a polar organic solvent co-reagent so as to remove any protectinggroups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (VI), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (VI), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In an embodiment, a method of making a compound or derivative havingformula (VIa), or a salt, solvate, or prodrug thereof, can include thesteps of:

(a) providing a compound or derivative having formula (Va), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (1<x≤10) molar equivalent amountof a carbodiimide reagent, in the presence of water or an organicsolvent co-reagent in an amount of up to 10 molar equivalents;

optionally, (b1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, the compound or derivativehaving formula (3), or salt thereof, the carbodiimide reagent, and thewater or organic solvent co-reagent, with at least a catalytic amount ofa divalent metal salt;

(c) processing the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the carbodiimide reagent, the water or organicsolvent co-reagent, and, optionally, the divalent metal salt, so as toproduce the compound or derivative having formula (VIa), or salt,solvate, or prodrug thereof;

(d) adding, optionally, the compound or derivative having formula (Va),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, thecarbodiimide reagent, the water or organic solvent co-reagent,optionally, the divalent metal salt, and the compound or derivativehaving formula (VIa), or salt, solvate, or prodrug thereof, to icedwater;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (Va), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (VIa), or salt,solvate, or prodrug thereof; and

optionally, (e1) treating the compound or derivative having formula(VIa), or salt, solvate, or prodrug thereof, with deprotectionreagent(s) in a polar organic solvent co-reagent so as to remove anyprotecting groups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (VIa), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (VIa), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In another embodiment, a method of making a compound or derivativehaving formula (VIa), or a salt, solvate, or prodrug thereof, caninclude the steps of:

(a) providing a compound or derivative having formula (Va), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (0<x≤10) molar equivalent amountof an amine, in the presence of water or an organic solvent co-reagentin an amount of up to 10 molar equivalents;

optionally, (b1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, the compound or derivativehaving formula (3), or salt thereof, the amine, and the water or organicsolvent co-reagent, with at least a catalytic amount of a divalent metalsalt;

(c) processing the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the amine, the water or organic solventco-reagent, and, optionally, the divalent metal salt, so as to producethe compound or derivative having formula (VIa), or salt, solvate, orprodrug thereof;

(d) adding, optionally, the compound or derivative having formula (Va),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, the amine,the water or organic solvent co-reagent, optionally, the divalent metalsalt, and the compound or derivative having formula (VIa), or salt,solvate, or prodrug thereof, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (Va), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (VIa), or salt,solvate, or prodrug thereof; and

optionally, (e1) treating the compound or derivative having formula(VIa), or salt, solvate, or prodrug thereof, with deprotectionreagent(s) in a polar organic solvent co-reagent so as to remove anyprotecting groups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (VIa), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (VIa), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

In yet another embodiment, a method of making a compound or derivativehaving formula (VIa), or a salt, solvate, or prodrug thereof, caninclude the steps of:

(a) providing a compound or derivative having formula (Va), or a salt,solvate, or prodrug thereof;

(b) treating the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, with a compound or derivative havingformula (3), or a salt thereof, and a (0<x≤10) molar equivalent amountof a Brønsted acid, in the presence of water or an organic solventco-reagent in an amount of up to 10 molar equivalents;

optionally, (b1) treating the compound or derivative having formula(Va), or salt, solvate, or prodrug thereof, the compound or derivativehaving formula (3), or salt thereof, the Brønsted acid, and the water ororganic solvent co-reagent, with at least a catalytic amount of adivalent metal salt;

(c) processing the compound or derivative having formula (Va), or salt,solvate, or prodrug thereof, the compound or derivative having formula(3), or salt thereof, the Brønsted acid, the water or organic solventco-reagent, and, optionally, the divalent metal salt, so as to producethe compound or derivative having formula (VIa), or salt, solvate, orprodrug thereof;

(d) adding, optionally, the compound or derivative having formula (Va),or salt, solvate, or prodrug thereof, optionally, the compound orderivative having formula (3), or salt thereof, optionally, the Brønstedacid, the water or organic solvent co-reagent, optionally, the divalentmetal salt, and the compound or derivative having formula (VIa), orsalt, solvate, or prodrug thereof, to iced water;

optionally, (d1) adjusting the pH of the aqueous phase with an aqueousbase;

optionally, (d2) isolating the unreacted compound or derivative havingformula (Va), or salt, solvate, or prodrug thereof;

optionally, (d3) isolating the unreacted compound or derivative havingformula (3), or salt thereof;

(e) isolating the compound or derivative having formula (VIa), or salt,solvate, or prodrug thereof; and

optionally, (e1) treating the compound or derivative having formula(VIa), or salt, solvate, or prodrug thereof, with deprotectionreagent(s) in a polar organic solvent co-reagent so as to remove anyprotecting groups of R⁷, R⁸, R⁹, R¹⁰, Y¹, and/or W¹.

Processing can be carried out under batch processing conditions or bycontinuously processing. Continuously processing may include one or moremethods of agitation selected from the group consisting of continuousgrinding and extruding. Continuous grinding may be performed betweenabout 50 RPM and about 200 RPM, preferably between about 75 RPM andabout 150 RPM, and most preferably between about 100 RPM and about 130RPM.

The process described herein effects a preparation of a compound orderivative having formula (VIa), or salt, solvate, or prodrug thereof,under almost solventless conditions.

The polar organic solvent co-reagent employed in the above method ofmaking a compound or derivative having formula (VIa), or salt, solvate,or prodrug thereof, can be a polar organic solvent from among, forexample, preferably, the Class 2 Residual Solvents listed in Table 2, oroptionally, for non-human use, the Class 3 Residual Solvents listed inTable 3 in THE NATIONAL FORMULARY, UNITED STATES PHARMACOPEIA 30 <467>(U.S. PHARMACOPEIAL CONVENTION 2006) (USP 30 at <467>), incorporated byreference herein in its entirety.

It is understood that the pH can be adjusted to the isoelectric point ofthe product compound(s) or derivative(s), or near neutral pH.Precipitation of the product compound(s) or derivative(s) can be carriedout using an appropriate water miscible, or other generally non-toxic,solvent.

An embodiment of the chemoselective, and optionally stereoselective,synthesis of a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, optionally in a particular anomeric ratio(alpha/beta), is shown above in Scheme A.

An embodiment of the chemoselective synthesis of a compound orderivative having formula (I-H), or a salt, solvate, or prodrug thereof,is shown above in Scheme B.

An alternative embodiment of the chemoselective synthesis of a compoundor derivative having formula (I-H), or a salt, solvate, or prodrugthereof, is shown above in Scheme C.

An embodiment of the chemoselective synthesis of a compound orderivative having formula (II), or a salt, solvate, or prodrug thereof,is shown above in Scheme D.

An alternative embodiment of the chemoselective synthesis of a compoundor derivative having formula (II), or a salt, solvate, or prodrugthereof, is shown above in Scheme E.

An embodiment of the chemoselective synthesis of a compound orderivative having formula (III), or a salt, solvate, or prodrug thereof,is shown above in Scheme F.

An embodiment of the chemoselective, and optionally stereoselective,synthesis of a compound or derivative having formula (IV), or a salt,solvate, or prodrug thereof, is shown above in Scheme G.

An embodiment of the chemoselective synthesis of a compound orderivative having formula (IV-H), or a salt, solvate, or prodrugthereof, is shown above in Scheme H.

An alternative embodiment of the chemoselective synthesis of a compoundor derivative having formula (IV-H), or a salt, solvate, or prodrugthereof, is shown above in Scheme I.

An embodiment of the chemoselective synthesis of a compound orderivative having formula (V), or a salt, solvate, or prodrug thereof,is shown above in Scheme J.

An alternative embodiment of the chemoselective synthesis of a compoundor derivative having formula (V), or a salt, solvate, or prodrugthereof, is shown above in Scheme K.

An embodiment of the chemoselective synthesis of a compound orderivative having formula (VI), or a salt, solvate, or prodrug thereof,is shown above in Scheme L.

In the embodiments shown above in Schemes A-L:

optionally wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻is selected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate;

optionally wherein when X⁻ is absent, optionally the counterion is aninternal salt;

optionally X⁻ is an anion of a substituted or unsubstituted carboxylicacid selected from a monocarboxylic acid, a dicarboxylic acid, or apolycarboxylic acid; and,

optionally X⁻ is an anion of a substituted monocarboxylic acid, furtheroptionally an anion of a substituted propanoic acid (propanoate orpropionate), or an anion of a substituted acetic acid (acetate), or ananion of a hydroxyl-propanoic acid, or an anion of 2-hydroxypropanoicacid (being lactic acid, the anion of lactic acid being lactate), or atrihaloacetate selected from trichloroacetate, tribromoacetate, andtrifluoroacetate; and,

optionally X⁻ is an anion of an unsubstituted monocarboxylic acidselected from formic acid, acetic acid, propionic acid, or butyric acid,being formate, acetate, propionate, and butyrate, respectively; and,

optionally X⁻ is an anion of a substituted or unsubstituted amino acid,i.e., amino-monocarboxylic acid or an amino-dicarboxylic acid,optionally selected from glutamic acid and aspartic acid, beingglutamate and aspartate, respectively; and,

optionally X⁻ is an anion of ascorbic acid, being ascorbate; and,

optionally X⁻ is a halide selected from fluoride, chloride, bromide, oriodide; and,

optionally X⁻ is an anion of a substituted or unsubstituted sulfonate,further optionally a trihalomethanesulfonate selected fromtrifluoromethanesulfonate, tribromomethanesulfonate, ortrichloromethanesulfonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted carbonate,further optionally hydrogen carbonate; and,

optionally X⁻ is an anion of a substituted or unsubstituted glutathioneor glutathione disulfide;

wherein the substituted carboxylic acid, substituted monocarboxylicacid, substituted propanoic acid, substituted acetic acid, substitutedamino acid, substituted sulfonate, substituted carbonate, substitutedglutathione, and substituted glutathione disulfide are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein X′ is selected from the group consisting of fluoro, chloro,bromo, iodo, HCO₂, acetoxy, propionoxy, butyroxy, glutamyloxy,aspartyloxy, ascorbyloxy, benzoxy, HOCO₂, citryloxy, carbamyloxy,gluconyloxy, lactyloxy, methyl bromo, methyl sulfoxy, nitrate,phosphate, diphosphate, succinyloxy, sulfoxy, trifluoromethanesulfoxy,trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy;

each Y¹ and Y² is independently selected from the group consisting ofhydrogen, sodium, potassium, lithium, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2),niacin (vitamin B3), pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, substituted heterocycle, andsubstituted amino are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, Y¹ and Y² taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each W¹ and W² is independently selected from the group consisting ofhydrogen, sodium, potassium, lithium, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2),niacin (vitamin B3), pyridoxine (vitamin B6), —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, substituted heterocycle, andsubstituted amino are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, W¹ and W² taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

or, alternatively, Y¹ and W¹ taken together are selected from the groupconsisting of sodium, potassium, lithium, magnesium, calcium, strontium,barium, and substituted or unsubstituted 2-(methylenyl)phenyl; whereinthe substituted 2-(methylenyl)phenyl is substituted with one to foursubstituents independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂,—C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

optionally wherein Y³ is oxygen, sulfur, or absent;

optionally wherein W³ is oxygen, sulfur, or absent;

each of Z¹ and Z² is independently NH or oxygen;

each of Z³, Z⁴, Z⁵, and Z⁶ is independently nitrogen or oxygen;

m is 1 or 2;

n is 0 or 1;

q is 1 or 2;

t is 1 or 2;

u is 1 or 2;

each R¹ is independently selected from the group consisting of hydrogen,substituted or unsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, and substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester,aryl(C₁-C₄)alkyl, heterocycle(C₁-C₄)alkyl, TMS, —N(R^(A))—CO₂R^(C),—N(R^(A))—CO₂R^(B), —C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B);wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, and substituted heterocycleare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein when R¹ is hydrogen, Z² is oxygen, m is 1, and n is 0, thecompound or derivative may optionally take the form of the carboxylateanion conjugate base species of the compound or derivative, furtheroptionally associated with a positively charged counterion selected fromthe group consisting of alkali metal, alkaline earth metal, transitionmetal, and base addition cations;

R^(A) is selected from the group consisting of —H, —(C₁-C₆)alkyl,—(CH₂)₃—NH—C(NH₂)(═NH), —CH₂C(═O)NH₂, —CH₂COOH, —CH₂SH,—(CH₂)₂C(═O)—NH₂, —(CH₂)₂COOH, —CH₂-(2-imidazolyl), —CH(CH₃)—CH₂—CH₃,—CH₂CH(CH₃)₂, —(CH₂)₄—NH₂, —(CH₂)₂—S—CH₃, phenyl, —CH₂-phenyl, —CH₂—OH,—CH(OH)—CH₃, —CH₂-(3-indolyl), —CH₂-(4-hydroxyphenyl), —CH(CH₃)₂, —NH₂,and —CH₂—CH₃;

each R^(B) is independently hydrogen or —(C₁-C₈)alkyl;

each R^(C) is independently selected from the group consisting ofhydrogen, —(C₁-C₈)alkyl, substituted or unsubstituted pyridyl,substituted or unsubstituted 1,4-dihydropyridyl, a radical of a compoundor derivative having formula (I), and vitamin B7 ester (biotinyl);wherein the substituted pyridyl and substituted 1,4-dihydropyridyl aresubstituted with one to five substituents independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,halogen, —CN, —NO₂, —C(O)R^(B), —C(O)OR^(B), —C(O)NR^(B) ₂,—C(═NR^(B))NR^(B) ₂, —OR^(B), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl,—OC(O)NR^(B) ₂, —(C₁-C₆)alkylene-NR^(B) ₂, —NR^(B) ₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)O(C₁-C₆)alkyl, —NR^(B)C(O)NR^(B) ₂, —NR^(B)SO₂NR^(B) ₂,—SR^(B), —S(O)R^(B), —SO₂R^(B), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(B) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(B);

R² and R³ are each independently selected from the group consisting ofhydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN,—NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁴ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

wherein C* has an absolute configuration of R or S, or a mixture of Rand S;

R⁵ is selected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁶ is selected from the group consisting of hydrogen, —C(O)R′, —C(O)OR′,—C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl, substituted orunsubstituted (C₁-C₈)cycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitaminB6 ester, choline ester, biotin ester, vitamin A ester, resveratrolester, glutathione ester, glutathione disulfide ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R′ is selected from the group consisting of hydrogen, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₁-C₈)cycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle,vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester,biotin ester, vitamin A ester, resveratrol ester, aryl(C₁-C₄)alkyl,heterocycle(C₁-C₄)alkyl, —N(R^(A))—CO₂R^(C), —N(R^(A))—CO₂R^(B),—C**H—(R^(A))—NH₂, and —C**H—(R^(A))—CO₂R^(B); wherein the substituted(C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl, substituted aryl,substituted heteroaryl, and substituted heterocycle are substituted withone to five substituents independently selected from the groupconsisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen,—CN, —NO₂, —C(O)R^(C), —C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂,—OR^(C), —OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹¹ is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, substituted or unsubstituted heterocycle(C₁-C₄)alkyl;wherein the substituted (C₁-C₈)alkyl, substituted (C₁-C₈)cycloalkyl,substituted aryl, substituted heteroaryl, substituted heterocycle,substituted aryl(C₁-C₄)alkyl, and substituted heterocycle(C₁-C₄)alkylare substituted with one to five substituents independently selectedfrom the group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C), —C(O)OR^(C),—C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C), —OC(O)(C₁-C₆)alkyl,—OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂, —(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C)₂, —NR^(C)C(O)R^(C), —NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂,—NR^(C)SO₂NR^(C) ₂, —SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl,—SO₂NR^(C) ₂, —(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

R¹² is selected from the group consisting of hydrogen, —C(O)R′,—C(O)OR′, —C(O)NHR′, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₁-C₈)cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocycle, substituted or unsubstitutedaryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

each R¹³ is independently selected from the group consisting ofhydrogen, —C(O)R′, —C(O)OR′, —C(O)NHR′, substituted or unsubstituted(C₁-C₈)alkyl, substituted or unsubstituted (C₁-C₈)cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl(C₁-C₄)alkyl, and substituted or unsubstitutedheterocycle(C₁-C₄)alkyl; wherein the substituted (C₁-C₈)alkyl,substituted (C₁-C₈)cycloalkyl, substituted aryl, substituted heteroaryl,substituted heterocycle, substituted aryl(C₁-C₄)alkyl, and substitutedheterocycle(C₁-C₄)alkyl are substituted with one to five substituentsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, halogen, —CN, —NO₂, —C(O)R^(C),—C(O)OR^(C), —C(O)NR^(C) ₂, —C(═NR^(C))NR^(C) ₂, —OR^(C),—OC(O)(C₁-C₆)alkyl, —OC(O)O(C₁-C₆)alkyl, —OC(O)NR^(C) ₂,—(C₁-C₆)alkylene-NR^(C) ₂, —NR^(C) ₂, —NR^(C)C(O)R^(C),—NR^(C)C(O)O(C₁-C₆)alkyl, —NR^(C)C(O)NR^(C) ₂, —NR^(C)SO₂NR^(C) ₂,—SR^(C), —S(O)R^(C), —SO₂R^(C), —OSO₂(C₁-C₆)alkyl, —SO₂NR^(C) ₂,—(C₁-C₆)perfluoroalkyl, and —(C₁-C₆)alkylene-OR^(C);

provided that the absolute configuration of C** is R or S, or a mixtureof R and S.

As discussed above, the existing prior art approaches, for the mostpart, utilize solvent-mediated approaches to prepare the nicotinoylribosides and reduced nicotinoyl ribosides, modified derivativesthereof, phosphorylated analogs thereof, and adenylyl dinucleotideconjugates thereof. Such processes are cumbersome, inefficient, and notscalable.

As used herein, the terms “trimethylsilylating agent(s)” or“trimethylsilylating reagent(s),” alone or in combination with otherterms, refer to compounds that include one or more tetravalent siliconatoms each covalently bonded to three methyl groups (i.e.,trimethylsilyl (“TMS”) group) and, upon reaction with organic compoundscontaining an oxygen-hydrogen or nitrogen-hydrogen covalent bond, yieldan organic compound wherein the hydrogen of the oxygen-hydrogen ornitrogen-hydrogen covalent bond has been replaced with thetrimethylsilyl (TMS) group such that the silicon atom is insteadcovalently bonded to the oxygen or nitrogen. The trimethylsilylation ispreferably carried out by dissolving the organic compound in excessmolar equivalents of hexamethyldisilazane (“HMDS”) as atrimethylsilylating reagent, optionally with at least a catalytic amountof ammonium sulfate (“(NH₄)₂SO₄”). Preferred reaction conditions includea temperature of 0° C. to reflux and a time of about 2 hours to about 12hours. It is noted that trimethylsilylation can also be carried out bydissolving an organic compound in an organic solvent and reacting itwith excess trimethylsilyl chloride in the presence of an excess oforganic amine base, for example, triethylamine (“Et₃N” or “TEA”),optionally further in the presence of HMDS. It is noted thattrimethylsilylation can alternatively be carried out by using excessbis(trimethylsilyl)acetamide (“BSA”) as a trimethylsilylating reagent.The person skilled in the art knows further processes that can be usedto introduce trimethylsilyl groups, because trimethylsilylating agent(s)and reagent(s) have been extensively documented in the chemicalliterature.

As used herein, the terms “phosphorylating agent” or “phosphorylatingreagent,” alone or in combination with other terms, refer to compoundsthat include a phosphorus atom in the +5 oxidation state and, uponreaction with hydroxyl-containing compounds, yield a phosphate triester.

One suitable phosphorylating agent or reagent is phosphorus oxychloride(POCl₃). Other suitable phosphorylating agents or reagents (orphosphorus reagent systems) include compounds having formulaP(O)C₁(OR^(X))(OR^(Y)) that include CAS Numbers 2524-64-3, 6609-64-9,814-49-3, 14254-41-2, 2574-25-6, 813-77-4, 1499-17-8, 2510-89-6,819-43-2, 5381-98-6, 538-37-4, 57188-46-2, 81639-99-8, 17672-53-6,4090-55-5, 17776-78-2, 6630-13-3, 56119-60-9, 77075-54-8, 89104-48-3,6546-97-0, 6630-15-5, 16383-57-6, 381-44-2, 124648-60-8, 17788-08-8,58377-73-4, 6630-14-4, 17158-87-1, 17677-92-8, 51103-92-5, 52258-06-7,56623-07-5, 58377-74-5, 85363-77-5, 112966-13-9, 167907-25-7,179695-78-4, 877458-32-7, 1424937-89-2, 1424939-04-7, 2035-83-8,127164-51-6, 6719-79-5, 59819-52-2, 69919-18-2, 77181-80-7, 4040-23-7,6533-33-1, 6719-82-0, 6719-84-2, 22939-24-8, 27315-40-8, 28888-24-6,61550-37-6, 73992-66-2, 86531-53-5, 96357-53-8, 108249-87-2,343863-91-2, 875893-99-5, 714-87-4, 6087-94-1, 13674-83-4, 56883-17-1,88805-00-9, 92401-83-7, 93115-98-1, 120628-26-4, 130312-59-3,315179-27-2, 1388636-60-9, 1388636-61-0; and compounds having formulaP(O)Cl₂(OR^(Z)) that include CAS Numbers 770-12-7, 1498-51-7,15074-54-1, 777-52-6, 677-24-7, 772-79-2, 4167-02-6, 1455-05-6,31651-76-0, 53676-22-5, 18868-46-7, 53676-18-9, 940-18-1, 84681-46-9,878-17-1, 105053-57-4, 149864-64-2, 6964-36-9, 18350-98-6, 53676-17-8,60223-35-0, 25359-51-7, 2035-84-9, 2196-02-3, 382608-79-9, 775-08-6,30333-08-5, 1479-10-3, 2213-71-0, 5305-82-8, 5995-77-7, 13674-82-3,13825-97-3, 17788-07-7, 19430-76-3, 19430-77-4, 20056-41-1, 20464-68-0,31735-82-7, 36196-79-9, 41998-90-7, 52198-45-5, 53121-39-4, 53121-41-8,99884-77-2, 105053-58-5, 125440-36-0, 140468-02-6, 140468-03-7,184528-24-5, 870673-87-3, 916893-01-1, 1498-52-8, 20464-67-9,38135-34-1, 41240-73-7, 62485-00-1, 78840-91-2, 313946-12-2,1242826-74-9. R^(X), R^(Y), and R^(Z) may be the same or different, andinclude, but are not limited to, simple alkyl.

As used herein, the terms “phosphitylating agent” or “phosphitylatingreagent,” alone or in combination with other terms, refer to compoundsthat include a phosphorus atom in the +3 oxidation state and, uponreaction with hydroxyl-containing compounds, yield a phosphite triester.

As used herein, the term “thiophosphorylating agent,” alone or incombination with other terms, refers to compounds that include aphosphorus atom in the +5 oxidation state and with a bond to a sulfuratom, and which, upon reaction with hydroxyl-containing compounds, yielda thiophosphate triester. One suitable thiosphorylating reagent isphosphoryl thiochloride (P(S)Cl₃).

As used herein, the term “carbodiimide reagent,” alone or in combinationwith other terms, refers to alkylcarbodiimide reagents, including, butnot limited to, dicyclohexylcarbodiimide (“DCC”),diisopropylcarbodiimide (“DCI”), andethyl-(N′,N′-dimethylamino)propylcarbodiimide hydrochloride (“EDC”).Without being bound by theory, it is believed that carbodiimide reagentscan activate one phosphate monoester for displacement with another, withsubsequent formation of a pyrophosphate linkage.

As used herein, the term “divalent metal salt,” alone or in combinationwith other terms, refers to ionic compounds that include a cationicspecies arising from a metallic element that can attain a formal chargeof +2 (i.e., “divalent”). Such metallic elements include, but are notlimited to zinc (i.e., “Zn⁺²”), magnesium (i.e., “Mg⁺²”), manganese(i.e., “Mn⁺²”), and cadmium (i.e., “Cd⁺²”). Without being bound bytheory, it is believed that divalent metal salts will facilitate thereaction of activated monophosphates as, for example, morpholidates orphosphoroimidazolates, with another monophosphate, to achieve thedesired pyrophosphate linkage and produce the desired adenylyldinucleotide conjugate.

Without being bound by theory, it is believed that a monophosphate canbe activated as a phosphoramidate by reaction with an appropriate amine.The activated monophosphate could then be reacted with anothermonophosphate to achieve the desired pyrophosphate linkage and producethe desired adenylyl dinucleotide conjugate. Non-limiting examples ofamines include, for example, morpholine, and other amines that arepresently disclosed herein. Alternatively, without being bound bytheory, it is believed that a monophosphate can be activated by reactionwith an acid, in an amount ranging from catalytic amounts up tostoichiometric or molar equivalent amounts. Non-limiting examples ofacids are presently disclosed herein.

The person of ordinary skill in the art knows further processes that canbe used to introduce pyrophosphate linkages, because conditions andreagents for the syntheses of pyrophosphate linkages have beenextensively documented in the chemical literature.

The compounds or derivatives having formulae (2), (I), (I-H), (II),(III), (IV), (IV-H), (V), and/or (VI), or salts, solvates, or prodrugsthereof, synthesized by the methods of the present disclosure, andintermediates, may be isolated from their reaction mixtures and purifiedby standard techniques such as filtration, liquid-liquid extraction,solid phase extraction, distillation, recrystallization, orchromatography, including flash column chromatography, preparative TLC,HPTLC, HPLC, or rp-HPLC. One preferred method for purification of thecompounds or derivatives having formulae (2), (I), (I-H), (II), (III),(IV), (IV-H), (V), and/or (VI), or salts, solvates, or prodrugs thereof,comprises crystallizing the compound or derivative, or salt, solvate, orprodrug thereof, from a solvent, to form, preferably, a crystalline formof the compound or derivative, or salt, solvate, or prodrug thereof.Following crystallization, the crystallization solvent is removed by aprocess other than evaporation, for example, filtration or decanting,and the crystals are then preferably washed using pure solvent (or amixture of pure solvents). Preferred solvents for crystallizationinclude water; alcohols, particularly alcohols containing up to fourcarbon atoms, such as methanol, ethanol, isopropanol, butan-1-ol,butan-2-ol, and 2-methyl-2-propanol; ethers, for example diethyl ether,diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxyethane,tetrahydrofuran, and 1,4-dioxane; carboxylic acids, for example formicacid and acetic acid; hydrocarbon solvents, for example pentane, hexane,and toluene; and mixtures thereof, particularly aqueous mixtures such asaqueous methanol, ethanol, isopropanol, and acetone. Pure solvents,preferably at least analytical grade, and more preferably pharmaceuticalgrade are preferably used. In a preferred embodiment of the processes ofthe invention, the products are so isolated. In the compounds orderivatives having formulae (2), (I), (I-H), (II), (III), (IV), (IV-H),(V), and/or (VI), or salts, solvates, or prodrugs thereof, synthesizedby the methods of the present disclosure, the compounds or derivativeshaving formula (2), (I), (I-H), (II), (III), (IV), (IV-H), (V), and/or(VI), or salts, solvates, or prodrugs thereof, synthesized by themethods of the present disclosure, are preferably in or prepared from acrystalline form, preferably prepared according to such a process.Alternatively, the compounds or derivatives having formulae (2), (I),(I-H), (II), (III), (IV), (IV-H), (V), and/or (VI), or salts, solvates,or prodrugs thereof, synthesized by the methods of the presentdisclosure, can be isolated using lyophilization or freeze-dryingtechniques, following ion-exchange purification, thus avoiding use ofnon-aqueous solvents.

The synthetic methods described above reflect a convergent synthesisstrategy. Thus, two components may be synthesized and elaboratedseparately prior to condensing or coupling the compounds to form thetarget compounds. These convergent synthetic schemes allow forarrangement of the assembly steps of the backbone of the targetcompounds and derivatization of derivatizable functionalities toaccommodate functional group sensitivity and/or to allow for functionalgroups or elements to be introduced either before or after the assemblyof the backbone of the target compounds via the condensation or couplingreactions described.

It will be appreciated by one skilled in the art that certain aromaticsubstituents in compounds synthesized by the methods of the presentdisclosure, intermediates used in the processes above, or precursors tothe compounds synthesized by the methods of the present disclosure, maybe introduced by employing aromatic substitution reactions to introduceor replace a substituent, or by using functional group transformationsto modify an existing substituent, or a combination thereof. Suchreactions may be effected either prior to or immediately following theprocesses mentioned above, and are included as part of the processaspect of the invention. The reagents and reaction conditions for suchprocedures are known in the art. Specific examples of procedures thatmay be employed include, but are not limited to, electrophilicfunctionalization of an aromatic ring, for example via nitration,halogenation, or acylation; transformation of a nitro group to an aminogroup, for example via reduction, such as by catalytic hydrogenation;acylation, alkylation, or sulfonylation of an amino or hydroxyl group;replacement of an amino group by another functional group via conversionto an intermediate diazonium salt followed by nucleophilic or freeradical substitution of the diazonium salt; or replacement of a halogenby another group, for example via nucleophilic ororganometallically-catalyzed substitution reactions.

Additionally, in the aforesaid processes, certain functional groups thatwould be sensitive to the reaction conditions may be protected byprotecting groups. A protecting group is a derivative of a chemicalfunctional group that would otherwise be incompatible with theconditions required to perform a particular reaction that, after thereaction has been carried out, can be removed to regenerate the originalfunctional group, which is thereby considered to have been “protected.”Any chemical functionality that is a structural component of any of thereagents used to synthesize compounds synthesized by the methods of thepresent disclosure may be optionally protected with a chemicalprotecting group if such a protecting group is useful in the synthesisof compounds synthesized by the methods of the present disclosure. Theperson skilled in the art knows when protecting groups are indicated,how to select such groups, and processes that can be used forselectively introducing and selectively removing them, because methodsof selecting and using protecting groups have been extensivelydocumented in the chemical literature. Techniques for selecting,incorporating, and removing chemical functional groups may be found, forexample, in THEODORA W. GREENE & PETER G. M. WUTS, PROTECTIVE GROUPS INORGANIC SYNTHESIS (John Wiley & Sons, Inc. 1999), the entire disclosureof which is incorporated herein by reference.

In addition to use of a protecting group, sensitive functional groupsmay be introduced as synthetic precursors to the functional groupsdesired in the intermediate or final product. An example of this is anaromatic nitro (—NO₂) group. The aromatic nitro group does not undergoany of the nucleophilic reactions of an aromatic amino group. However,the nitro group can serve as the equivalent of a protected amino groupbecause it is readily reduced to the amino group under mild conditionsthat are selective for the nitro group over most other functionalgroups.

It will be appreciated by one skilled in the art that the processesdescribed are not the exclusive means by which compounds synthesized bythe methods of the present disclosure may be synthesized and that anextremely broad repertoire of synthetic organic reactions is availableto be potentially employed in synthesizing compounds synthesized by themethods of the present disclosure. The person skilled in the art knowshow to select and implement appropriate synthetic routes. Suitablesynthetic methods may be identified by reference to the literature,including reference sources such as COMPREHENSIVE ORGANIC SYNTHESIS (B.M. Trost & I. Fleming eds., Pergamon Press 1991); COMPREHENSIVE ORGANICFUNCTIONAL GROUP TRANSFORMATIONS (A. R. Katritzky, O. Meth-Cohn, & C. W.Rees eds., Pergamon Press 1996); COMPREHENSIVE ORGANIC FUNCTIONAL GROUPTRANSFORMATIONS II (A. R. Katritzky & R. J. K. Taylor eds., 2d ed.,Elsevier 2004); COMPREHENSIVE HETEROCYCLIC CHEMISTRY (A. R. Katritzky &C. W. Rees eds., Pergamon Press 1984); COMPREHENSIVE HETEROCYCLICCHEMISTRY II (A. R. Katritzky, C. W. Rees, & E. F. V. Scriven eds.,Pergamon Press 1996); and J. MARCH, ADVANCED ORGANIC CHEMISTRY (4th ed.,John Wiley & Sons, Inc. 1992).

Salts of Compounds or Derivatives Synthesized According to the Methodsof the Present Disclosure

The compounds or derivatives synthesized by the methods of the presentdisclosure may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases that are compounds orderivatives synthesized by the methods of the present disclosure. Theterm “pharmaceutically acceptable salt” refers to salts that possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications.

Suitable pharmaceutically acceptable acid solution salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids,examples of which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoroacetic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic,p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic,alginic, β-hydroxybutyric, salicylic, galactaric, and galacturonic acid.In the present examples of compounds or derivatives having formulae (2),(I), (I-H), (II), (III), (IV), (IV-H), (V), or (VI), or salts, solvates,or prodrugs thereof, i.e., compounds containing amino groups, pyridine,or reduced pyridine, said compounds can be isolated as salts ofinorganic acids or strong organic acids, e.g., hydrochloric acid ortrifluoroacetic acid.

Suitable pharmaceutically acceptable base addition salts of compounds orderivatives synthesized by the methods of the present disclosureinclude, for example, metallic salts including alkali metal, alkalineearth metal, and transition metal salts such as, for example, calcium,magnesium, potassium, sodium, and zinc salts. Further, base additionsalts of compounds synthesized by the methods of the present disclosureinclude, for example, ammonium salts. Pharmaceutically acceptable baseaddition salts also include organic salts made from basic amines suchas, for example, N,N-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumine (N-methylglucamine),tromethamine (tris(hydroxymethyl)aminomethane), and procaine.

All of these salts may be prepared by conventional means from thecorresponding compounds or derivatives having formulae (2), (I), (I-H),(II), (III), (IV), (IV-H), (V), (VI), or salts, solvates, or prodrugsthereof, by reacting, for example, the appropriate acid or base with thecompound or derivative having formulae (2), (I), (I-H), (II), (III),(IV), (IV-H), (V), or (VI), or salts, solvates, or prodrugs thereof.Preferably, the salts are in crystalline form, or alternatively in driedor freeze-dried form. The person skilled in the art will know how toprepare and select suitable salt forms for example, as described in P.H. STAHL & C. G. WERMUTH, HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES,SELECTION, AND USE (Wiley-VCH 2002).

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates a biologically activecompound as a result of spontaneous chemical reaction(s), enzymecatalyzed chemical reaction(s), and/or metabolic chemical reaction(s),or a combination of each. Standard prodrugs are formed using groupsattached to functionality, e.g., —OH, —SH, —COOH, —NR₂, associated withthe drug, that cleave in vivo. Standard prodrugs include, but are notlimited to, carboxylate esters where the group is alkyl, aryl, aralkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl, as well as esters of hydroxyl,thiol, and amines where the group attached is an acyl group, analkoxycarbonyl, aminocarbonyl, phosphate, or sulfate. The groupsillustrated are exemplary, not exhaustive, and one skilled in the artcould prepare other known varieties of prodrugs. Such prodrugs of thecompounds or derivatives having formula (I), (I-H), (II), (III), (IV),(IV-H), (V), and/or (VI) fall within the scope of the methods of thepresent invention. Prodrugs must undergo some form of a chemicaltransformation to produce the compound or derivative that isbiologically active or is a precursor of the biologically activecompound. In some cases, the prodrug is biologically active, usuallyless than the drug itself, and serves to improve drug efficacy or safetythrough improved oral bioavailability, pharmacodynamic half-life, etc.As used herein, the term “derivative,” alone or in combination withother terms, can include a prodrug.

The nutraceutical compositions of the present disclosure may beadministered in combination with a nutraceutically acceptable carrier.The active ingredients in such formulations may comprise from 1% byweight to 99% by weight, or alternatively, 0.1% by weight to 99.9% byweight. “Nutraceutically acceptable carrier” means any carrier,diluents, or excipient that is compatible with the other ingredients ofthe formulation and not deleterious to the user. In accordance with oneembodiment, suitable nutraceutically acceptable carriers can includeethanol, aqueous ethanol mixtures, water, fruit, and/or vegetablejuices, and combinations thereof.

Delivery System

Suitable dosage forms include tablets, capsules, solutions, suspensions,powders, gums, and confectionaries. Sublingual delivery systems include,but are not limited to, dissolvable tabs under and on the tongue, liquiddrops, and beverages. Edible films, hydrophilic polymers, oraldissolvable films, or oral dissolvable strips can be used. Other usefuldelivery systems comprise oral or nasal sprays or inhalers, and thelike.

For oral administration, a compound or derivative having formulae (2),(I), (I-H), (II), (III), (IV), (IV-H), (V), or (VI), or a salt, solvate,or prodrug thereof may be further combined with one or more solidinactive ingredients for the preparation of tablets, capsules, pills,powders, granules, or other suitable dosage forms. For example, theactive agent may be combined with at least one excipient such asfillers, binders, humectants, disintegrating agents, solution retarders,absorption accelerators, wetting agents, absorbents, or lubricatingagents. Other useful excipients include magnesium stearate, calciumstearate, mannitol, xylitol, sweeteners, starch, carboxymethylcellulose,microcrystalline cellulose, silica, gelatin, silicon dioxide, and thelike.

The compounds or derivatives synthesized by the methods of the presentdisclosure, together with a conventional adjuvant, carrier, or diluents,may thus be placed into the form of pharmaceutical compositions and unitdosages thereof. Such forms include solids, and in particular, tablets,filled capsules, powder, and pellet forms, and liquids, in particularaqueous or non-aqueous solutions, suspensions, emulsions, elixirs, andcapsules filled with the same, all for oral use, suppositories forrectal administration, and sterile injectable solutions for parenteraluse. Such pharmaceutical compositions and unit dosage forms thereof maycomprise conventional ingredients in conventional proportions, with orwithout additional active compounds or principals, and such unit dosageforms may contain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed.

The compounds or derivatives synthesized by the methods of the presentdisclosure can be administered in a wide variety of oral and parenteraldosage forms. It will be obvious to those skilled in the art that thefollowing dosage forms may comprise, as the active component, either achemical compound or derivative synthesized by the methods of thepresent disclosure or a pharmaceutically acceptable salt, solvate, orprodrug of a chemical compound or derivative synthesized by the methodsof the present disclosure.

For preparing pharmaceutical compositions from a chemical compound orderivative synthesized by the methods of the present disclosure,pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances that may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active components. In tablets, the activecomponent is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets preferably contain from about five or ten toabout seventy percent of the active compound(s) or derivative(s)synthesized by the methods of the present disclosure. Suitable carriersare microcrystalline cellulose, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like, and other excipients mayinclude magnesium stearate, stearic acid, talc, silicon dioxide, etc.The term “preparation” is intended to include the formulation of activecompound with encapsulating material as carrier providing a capsule inwhich the active component, with or without carriers, is surrounded by acarrier, which is thus in association with it. Tablets, powders,capsules, pills, sachets, and lozenges are included. Tablets, powders,capsules, pills, sachets, and lozenges can be used as solid formssuitable for oral administration.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. The chemical compounds orderivatives synthesized by the methods of the present disclosure maythus be formulated for parenteral administration (e.g., by injection,for example bolus injection or continuous infusion) and may be presentedin unit dose for example in ampoules, pre-filled syringes, small volumeinfusion, or in multi-dose containers with an added preservative). Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulation agents such assuspending, stabilizing, and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution, for constitutionwith a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents, as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,or other well-known suspending agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavored base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerine or sucrose and acacia; andmouthwashes comprising the active ingredient in suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette, or spray. Thecompositions may be provided in single or multi-dose form. Incompositions intended for administration to the respiratory tract,including intranasal compositions, the compound or derivative willgenerally have a small particle size, for example, of the order of 5microns or less. Such a particle size may be obtained by means known inthe art, for example by micronization.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets, capsules, and lozenges for oral administration and liquids fororal use are preferred compositions. Solutions or suspensions forapplication to the nasal cavity or to the respiratory tract arepreferred compositions. Transdermal patches for topical administrationto the epidermis are preferred.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences (MackPublishing Co., Easton, Pa.).

Solid nutritional compositions for oral administration may optionallycontain, in addition to the above enumerated nutritional compositioningredients or compounds: carrier materials such as corn starch,gelatin, acacia, microcrystalline cellulose, kaolin, dicalciumphosphate, calcium carbonate, sodium chloride, alginic acid, and thelike; binders including acacia, methylcellulose, sodiumcarboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, ethyl cellulose, and the like; and lubricants such asmagnesium stearate, stearic acid, silicone fluid, talc, waxes, oils,colloidal silica, and the like. The usefulness of such excipients iswell known in the art.

Liquid nutritional compositions for oral administration in connectionwith a method for preventing and/or treating inflammation, colds, and/orflu can be prepared in water or other aqueous vehicles. In addition tothe above enumerated ingredients or compounds, liquid nutritionalcompositions can include suspending agents such as, for example,methylcellulose, alginates, tragacanth, pectin, kelgin, carrageenan,acacia, polyvinylpyrrolidone, polyvinyl alcohol, and the like. Theliquid nutritional compositions can be in the form of a solution,emulsion, syrup, gel, or elixir including or containing, together withthe above enumerated ingredients or compounds, wetting agents,sweeteners, and coloring and flavoring agents. Various liquid and powdernutritional compositions can be prepared by conventional methods.Various ready-to-drink formulations (“RTDs”) are contemplated.

Routes of Administration

The compositions may be administered by any suitable route, includingbut not limited to oral, sublingual, buccal, ocular, pulmonary, rectal,and parenteral administration, or as an oral or nasal spray (e.g.,inhalation of nebulized vapors, droplets, or solid particles).Parenteral administration includes, for example, intravenous,intramuscular, intraarterial, intraperitoneal, intranasal, intravaginal,intravesical (e.g., to the bladder), intradermal, transdermal, topical,or subcutaneous administration. Also contemplated within the scope ofthe invention is the installation of a pharmaceutical composition in thebody of the patient in a controlled formulation, with systemic or localrelease of the drug to occur at a later time. For example, the drug maybe localized in a depot for controlled release to the circulation, orfor release to a local site.

Pharmaceutical compositions of the disclosure may be those suitable fororal, rectal, bronchial, nasal, pulmonal, topical (including buccal andsub-lingual), transdermal, vaginal, or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection, or infusion)administration, or those in a form suitable for administration byinhalation or insufflations, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing a compound or derivative synthesized bythe methods of the present disclosure, which matrices may be in the formof shaped articles, e.g., films or microcapsules.

The methods described above may be further understood in connection withthe following Examples. In addition, the following non-limiting examplesare provided to illustrate the invention. The illustrated syntheticpathways are applicable to other embodiments of the present invention.The synthetic procedures described as general methods describe what isbelieved will be typically effective to perform the synthesis indicated.However, the person skilled in the art will appreciate that it may benecessary to vary the procedures for any given embodiment of theinvention, e.g., vary the order or steps and/or the chemical reagentsused. Products may be purified by conventional techniques that willvary, for example, according to the amounts of side products producedthe physical properties of the compounds or derivatives synthesized bythe methods of the present invention.

Example 1 A. Synthetic Preparation of[(2R,3R,4R)-3,4-diacetoxy-5-chlorotetrahydrofuran-2-yl]methyl acetate(Compound 1): Compound of Formula (2): R⁶=R⁷=R⁸=Acetyl, X=Chloride

[(2R,3R,4R)-3,4,5-triacetoxytetrahydrofuran-2-yl]methyl acetate (100 g,314.19 mmol) was added to a 500 milliliter round-bottom flask andcharged with acetyl chloride (111.7 mL, 1579.96 mmol). The mixture wascooled to 0° C. using an ice bath, and ethanol (55.04 mL, 942.58 mmol)was added slowly, dropwise. Once all of the ethanol was added, thesolution was allowed to stir at 0° C. for one hour under sealedconditions. The reaction was judged to be complete by ¹H NMR, and themixture was carefully concentrated on the rotary evaporator. The product(91.3 g), Compound 1, was used without further purification for the nextstep. As seen in FIG. 1, NMR showed 87% conversion to the productchlororiboside triacetate (7% unreacted[(2R,3R,4R)-3,4,5-triacetoxytetrahydrofuran-2-yl]methyl acetate, and 6%α-chlororiboside triacetate). FIG. 5 compares ¹H NMR spectra ofrecovered, unreacted starting material([(2R,3R,4R)-3,4,5-triacetoxytetrahydrofuran-2-yl]methyl acetate)(bottom) and a quantitatively pure sample of the same chemical (top).

B. Synthetic Preparation of Nicotinamide Riboside Triacetate Chloride(Compound 2): Compound of Formula (Ia): R¹=Hydrogen, n=0, Z²=NH,R²=R³=R⁴=R⁵=Hydrogen, X⁻=Chloride, R⁶=R⁷=R⁸=Acetyl

To Compound 1 (86%, 92.59 g, 0.27 mol, 1 eq) was added nicotinamide (33g, 0.27 mol, 1 eq), and acetonitrile (84.67 mL, 1.62 mol, 6 eq), and theflask fitted with a reflux condenser and heated to 70° C. for 20minutes. ¹H NMR showed reaction to be complete. As seen in FIG. 2, ¹HNMR showed 93% conversion (determined by ¹H NMR integration), andapproximately 7% unreacted nicotinamide. The α:β anomeric ratio wasapproximately 4:6. It is expected that these results could be improvedupon if a proper sealed vessel were to be implemented. FIG. 3 depicts a¹H NMR spectra of the reaction mixture after removal of acetonitrilesolvent.

While still at 70° C., acetone was added (˜100 mL) and the reaction wasfiltered under vacuum. It is important to add the acetone immediatelyupon completion of the glycosylation reaction, when the reaction mixtureis still warm, followed by immediate filtration. The cake was washed afurther 2 times (2×100-150 mL) with acetone and then the solid wascollected and dried under high vacuum. The sample was subsequentlywashed with acetone until the white solid that had precipitated became afree-flowing white powder, which was then filtered under vacuum. Asshown in FIG. 4, ¹H NMR of the filtrate demonstrated that the whitepowder was the β-anomer of Compound 2 (approximately 54 g), which wasobtained as a free-flowing white powder. ¹H NMR demonstrated very smalltraces of α-anomer of Compound 2, and nicotinamide. These could beremoved by further washing with acetone, as visual inspection of thefinal product demonstrated some remaining small clumps therein.

The acetone washings became a viscous yellow oil as the sample becamemore concentrated, and white crystals began to precipitate. ¹H NMR weretaken of the white crystals after washing with ether to remove traces ofthe yellow oil, and the NMR showed the crystals to be tetraacetateriboside (unreacted from the synthetic preparation of Compound 1).Acetone has proven to be an effective solvent for separating β-anomer ofCompound 2 from α-anomer, as well as removing the other impurities.Multiple washings with acetone afforded pure β-anomer.

¹H NMR (400 MHz, MeOD): δ ppm 9.61 (s, 1H, aromatic), 9.30 (dt, J=6.3,1.4 Hz, 1H, aromatic), 9.10 (dt, J=8.2, 1.4 Hz, 1H, aromatic), 8.37 (dd,J=8.2, 6.3 Hz, 1H, aromatic), 6.60 (d, J=3.9 Hz, 1H, H-1 (anomeric)),5.60 (dd, J=5.6, 3.9 Hz, 1H, H-2), 5.46 (t, J=5.6 Hz, 1H, H-3),4.81-4.84 (m, 1H, H-4), 4.61 (AB_(X), J_(A,A′)=13.1 Hz, J_(A,B)=3.5 Hz,1H, H-5), 4.51 (AB_(X), J _(A,A′)=13.0 Hz, J_(A,B)=2.8 Hz, 1H, H-5′),2.20 (s, 3H, OAc), 2.17 (s, 3H, OAc), 2.16 (s, 3H, OAc). ¹³C NMR (100MHz, MeOD): δ ppm 172.1, 171.6, 171.2 (3×C(═O)CH₃), 164.9 (C(═O)NH₂),147.0, 144.3, 142.3, 136.2, 129.6 (aromatic), 99.4 (C-1 (anomeric)),84.4 (C-4), 77.6 (C-2), 70.7 (C-3), 63.5 (C-5).

The α-anomer of Compound 2 was isolated in order to get fullcharacterization and establish its physical appearance. As such, thecombined acetone washes were concentrated. FIG. 6 shows a ¹H NMRspectrum of the concentrated, combined acetone washes. The concentratedmaterial was loaded onto a 340 g silica biotage column with minimalMeOH. The gradient was run using 5% MeOH in EtOAc, increasing to 60%MeOH in EtOAc over approximately 2200 mL. The α-anomer of Compound 2 wasisolated as an off-white powder. As shown in FIG. 7, ¹H NMR stilldemonstrates some minor impurities of β-anomer of Compound 2 andnicotinamide. It is expected that further purification would afford pureα-anomer of Compound 2.

A range of reaction conditions have been explored, and are presented inTable 1, whereby extrusion was used in order to achieve the productionof Compound 2 from Compound 1 and nicotinamide (compound of formula(1)). Table 1 describes the conditions, including the use of additivessuch as microcrystalline cellulose (“MIC”) in order to achieve a betterflow at the addition state, as well as a better processing step result.While reaction occurred and seemed to have some effect on the α:βanomeric ratio of Compound 2, difficulties were encountered in terms ofcomplete conversion. These results demonstrate that extrusion issuitable for the continuous production of Compound 2 by extrusion withcurrently optimized yields above 85%, with the possibility of recyclingunreacted riboside tetraacetate.

TABLE 1 Summary of Glycosylation Study Conditions ¹H NMR ¹H NMR %mol:mol ratio integration integration ¹H NMR Conversion of β-anomer ofof α-anomer of β-anomer integration to Experiment Compound 1: Run(Compound (Compound of α:β Compound # nicotinamide # 2) 2) nicotinamideratio 2 1 1:1 — 1.05 1.00 5.92 1:1 54 250 RPM Room temp. 2 1:2 — 0.751.00 27.83 4:6 10 250 RPM Room temp. 3 1:1 — — — — — No 100 RPMconversion Room temp. 1:1 — 0.56 1.00 4.55 3.5:6.5 54 100 RPM 45° C. 1:1— 0.84 1.00 2.82 4.5:5.5 70 100 RPM 55° C. 1:0.5 — 0 1.00 7.94 0:1 46100 RPM 50° C. 1:0.5 — 0.58 1.00 1.84 4:6 85 100 RPM 50° C. (2nd cycle)1:0.5 — 0.44 1.00 9.91 3:7 50 50 RPM 50° C. 1:0.5 — 0.44 1.00 5.25 3:765 50 RPM 60° C. 1:0.5 — 0.50 1.00 3.33 3:7 75 250 RPM 60° C. 4 1:1 —0.77 1.00 43.02 4:6 12 100 RPM 50° C. 5 1:1 1 0.58 1.00 8.66 4:6 38 100RPM 2 0.88 1.00 5.53 1:1 54 50° C. 3 1.19 1.00 2.23 6:4 78 1 eq. MeCN 61:1 1 0.50 1.00 25.50 1:2 17 100 RPM 2 1.04 1.00 6.83 1:1 50 50° C. 31.36 1.00 4.71 6:4 63 0.5 eq. MeCN 7 1:1 1 — — 1 — — 100 RPM 2 0.77 1.0027.23 4:6 18 50° C. 3 1.26 1.00 8.38 6:4 47 1 eq. EtOAc 8 1:1.5 1 0.711.00 18.14 4:6 18 100 RPM 2 0.82 1.00 5.95 1:1 41 50° C. 3 1.08 1.003.76 1:1 56 1 eq. MeCN 9 1:1 1 — — — — — 100 RPM 2 — — — — — Room temp.3 — — — — — 1 eq. MeCN 4 — — — — — 10 1:1 1 0.44 1.00 8.46 3:7 37 100RPM 2 0.71 1.00 3.00 4:6 66 50° C. 3 0.57 1.00 3.58 4:6 60 1 eq. MeCN 40.62 1.00 3.97 4:6 60 MIC (mass:mass with nicotinamide) 11 1:1 1 0.471.00 8.08 3:7 38 100 RPM 2 0.73 1.00 2.98 4:6 66 70° C. 3 0.90 1.00 1.931:1 77 1 eq. MeCN 4 1.07 1.00 1.15 1:1 86 12 1:1 1 0.59 1.00 3.37 4:6 62100 RPM 2 0.62 1.00 3.21 4:6 63 70° C. 3 0.63 1.00 3.54 4:6 62 1 eq.MeCN MIC (mass:mass with nicotinamide) 13 1:1 1 0.33 1.00 4.14 1:3 52100 RPM 2 0.34 1.00 2.57 3:7 65 70° C. 3 0.39 1.00 2.96 3:7 63 2 eq.MeCN 4 0.39 1.00 2.45 3:7 66 MIC (mass:mass with nicotinamide) 14 1:1 10.24 1.00 3.98 2:8 51 100 RPM 2 0.37 1.00 3.26 3:7 59 70° C. 3 0.36 1.002.59 3:7 63 2 eq. MeCN 4 0.35 1.00 2.59 3:7 63 MIC (mass:mass withnicotinamide) 15 1:1 1 0.32 1.00 8.10 3:7 36 100 RPM 2 0.43 1.00 3.103:7 61 70° C. 3 0.59 1.00 2.06 4:6 67 2 eq. MeCN 4 0.54 1.00 1.74 4:6 75MIC (0.5 mass:mass with nicotinamide) 16 1:1 — 1.00 2.6 8.8 3:7 58 2 eq.MeCN MIC (mass:mass with nicotinamide) Ball mill (30 min, 30 Hz) 17 1:1— 1 1.8 4.1 4:6 70 2 eq. MeCN MIC (mass:mass with nicotinamide) 70° C.Solution-based 18 1:1 — 0.85 1.00 0.65 1:1 91 2 eq. MeCN 70° C.Solution-based 19 1:1 10 1 1.74 1.45 3:7 87 3 eq. MeCN min 70° C. 20 11.53 1.06 4:6 89 Solution-based min 30 1 1.50 1.00 4:6 90 min 60 1 1.420.96 4:6 90 min 20 1:1 10 1 1.52 1.06 4:6 89 2 eq. MeCN min 70° C. 20 11.41 0.87 4:6 90 Solution-based min 30 1 1.41 0.88 4:6 90 min 60 1 1.400.86 4:6 90 min

Crystalline Form I of nicotinamide riboside triacetate (NRTA) chloridemay be characterized by a powder X-ray diffraction pattern having peaksat 19.6, 22.1, and 26.6 degrees two theta±0.2 degrees two theta. Thecrystalline Form I of nicotinamide riboside triacetate (NRTA) chloridemay also or alternatively be characterized by a powder X-ray diffractionpattern having peaks at 9.8, 19.2, 19.6, 22.1, and 26.6 degrees twotheta±0.2 degrees two theta. The crystalline Form I of nicotinamideriboside triacetate (NRTA) chloride may also or alternatively becharacterized by a powder X-ray diffraction pattern having peaks at 9.8,14.5, 18.6, 19.2, 19.6, 22.1, 22.5, 26.6 degrees two theta±0.2 degreestwo theta.

In other embodiments, the crystalline Form I of nicotinamide ribosidetriacetate (NRTA) chloride may be characterized by a powder X-raydiffraction pattern substantially as shown in FIG. 18. The crystallineForm I of nicotinamide riboside triacetate (NRTA) chloride may also oralternatively be characterized by a powder X-ray diffraction patternhaving peaks substantially as provided in Table 2, below, ±0.2 degreestwo theta.

TABLE 2 Peak Pos. d-spacing Height I/I_(max) No. [°2 Th.] [Å] [cts] [%]1 4.911 17.978 319 13 2 9.787 9.03 1089 46 3 11.194 7.898 81 3 4 11.8057.49 283 12 5 12.623 7.007 89 4 6 14.199 6.232 331 14 7 14.48 6.112 77833 8 15.494 5.715 105 4 9 15.916 5.564 305 13 10 16.376 5.408 488 21 1118.602 4.766 702 30 12 19.239 4.6097 917 39 13 19.587 4.5286 1266 54 1421.769 4.0793 633 27 15 22.055 4.027 2363 100 16 22.474 3.9529 806 34 1722.792 3.898 232 10 18 23.995 3.706 270 11 19 25.496 3.491 211 9 2026.06 3.417 87 4 21 26.632 3.3444 1197 51 22 27.125 3.2848 362 15 2327.98 3.187 116 5 24 28.5 3.13 269 11 25 29.193 3.0566 339 14 26 30.972.885 66 3 27 34.866 2.5712 195 8 28 35.13 2.553 83 4 29 35.523 2.5251122 5 30 35.96 2.4953 314 13 31 38.91 2.313 39 2 32 39.6 2.274 115 5 3341.09 2.1947 185 8 34 43.52 2.078 72 3 35 44.234 2.0459 176 7 36 47.031.931 64 3

The crystalline Form I of nicotinamide riboside triacetate (NRTA)chloride may also or alternatively be characterized by a solid-state IRspectrum having peaks at 626.8, 644.1, and 916.0 cm⁻¹±0.2 cm⁻¹. Thecrystalline Form I of nicotinamide riboside triacetate (NRTA) chloridemay also or alternatively be characterized by a solid-state IR spectrumhaving peaks at 626.8, 644.1, 916.0, 1058.8, 1101.2, and 1114.7 cm⁻¹±0.2cm⁻¹. The crystalline Form I of nicotinamide riboside triacetate (NRTA)chloride may also or alternatively be characterized by a solid-state IRspectrum having peaks at 626.8, 644.1, 916.0, 1058.8, 1101.2, 1114.7,1205.3, 1240.0, 1683.6, and 1737.6 cm⁻¹±0.2 cm⁻¹. In certainembodiments, the crystalline Form I of nicotinamide riboside triacetate(NRTA) chloride may be characterized by a solid-state IR spectrumsubstantially as shown in FIG. 24. In further embodiments, thecrystalline Form I of nicotinamide riboside triacetate (NRTA) chloridemay be characterized by a solid-state IR spectrum having peakssubstantially as provided in Table 3, below, ±0.2 cm⁻¹.

TABLE 3 IR (cm⁻¹) 3276.52 3070.17 3004.60 2960.25 2910.10 1737.581683.58 1619.94 1602.58 1552.44 1494.59 1475.30 1459.87 1398.16 1378.881319.09 1294.02 1286.31 1240.03 1228.45 1205.31 1189.88 1114.67 1101.171058.75 1039.46 1024.03 991.25 950.75 927.61 916.04 892.89 781.04 746.33698.12 657.62 644.12 626.76 578.55

In another embodiment, crystalline Form I of nicotinamide ribosidetriacetate (NRTA) chloride is characterized by a DSC thermogram obtainedusing a heating rate of 10 K/min comprising an endothermic event with anonset temperature of 149° C.±2° C.

In yet another embodiment, crystalline Form I of nicotinamide ribosidetriacetate (NRTA) chloride is characterized by a DSC thermogram obtainedusing a heating rate of 10 K/min comprising an endothermic event with apeak temperature of 156° C.±2° C.

In yet another embodiment, crystalline Form I of nicotinamide ribosidetriacetate (NRTA) chloride is characterized by a DSC thermogram obtainedusing a heating rate of 10 K/min comprising an endothermic event with anonset temperature of 149° C.±2° C., a peak temperature of 156° C.±2° C.,or both.

In yet another embodiment, crystalline Form I of nicotinamide ribosidetriacetate (NRTA) chloride is characterized by a DSC thermogram obtainedusing a heating rate of 10 K/min comprising an endothermic event with anonset temperature of 208° C.±2° C.

In yet another embodiment, crystalline Form I of nicotinamide ribosidetriacetate (NRTA) chloride is characterized by a DSC thermogram obtainedusing a heating rate of 10 K/min comprising an endothermic event with apeak temperature of 215° C.±2° C.

In yet another embodiment, crystalline Form I of nicotinamide ribosidetriacetate (NRTA) chloride is characterized by a DSC thermogram obtainedusing a heating rate of 10 K/min comprising an endothermic event with anonset temperature of 208° C.±2° C., a peak temperature of 215° C.±2° C.,or both.

In yet another embodiment, crystalline Form I of nicotinamide ribosidetriacetate (NRTA) chloride may be characterized by a DSC thermogramsubstantially as shown in FIG. 31.

C. Synthetic Preparation of Nicotinamide Riboside Triflate (Compound 3):Compound of Formula (Ia): R¹=Hydrogen, n=0, Z²=NH, R²=R³=R⁴=R⁵=Hydrogen,X⁻=Triflate, R⁶=R⁷=R⁸=Acetyl

A range of reaction conditions have been explored, whereby extrusion wasused in order to achieve the production of Compound 3 from ribosidetetraacetate, TMSOTf, and nicotinamide. Table 1 describes the conditionsapplied to improve conversion. Reagent addition rate, extruder screwprofile, rotation speed, and temperature of the barrel affected thereaction outcomes and the α:β anomeric ratio of Compound 3. Forinstance, by increasing the extruder speed from 50 RPM to 250 RPM andthe residency time from 10 min to 15 min, the crude conversion yieldsincreased from 0 to 92%, as per evidence in FIGS. 12-14. These resultsdemonstrate that extrusion is suitable for the continuous production ofCompound 3 by extrusion with currently optimized yields above 92%, withthe possibility of recycling unreacted riboside tetraacetate.

D. Synthetic Preparation of Nicotinic Acid Riboside (Compound 4):Compound of Formula (Ia-H): R¹=Hydrogen, n=0, Z²=Oxygen,R²=R³=R⁴=R⁵=R⁶=R=R⁸=Hydrogen

To a dry round-bottom flask was added nicotinic acid (40 g, 324.9 mmol,1.0 equiv.), followed by HMDS (200 g, 1239.2 mmol, 3.8 equiv.) and acatalytic amount of ammonium sulphate (1% mol equiv.). The suspensionwas then heated to reflux under an atmosphere of nitrogen gas for 12hours. The solution was cooled to room temperature, and the excess HMDSwas removed under reduced pressure. The gummy oil was then resuspendedin freshly distilled dichloroethane (150 mL), followed by the additionof riboside tetraacetate (103 g, 322.6 mmol, 1.0 equiv.) and TMSOTf (58mL, 322.6 mmol, 1.0 equiv.). The solution was heated to 40° C. and leftstirring overnight under nitrogen gas. After NMR analysis indicated thatthe reaction had reached completion, the solution was allowed to cool toroom temperature. With intensive stirring, 100 mL of distilled water wasadded followed by the rapid addition of a saturated NaHCO₃ solution(approximately 50 mL). The pH was adjusted to approximately 6, and theorganic phase was separated, then the aqueous layer was washed threeadditional times with dichloromethane (100 mL), the aqueous layer wasthen frozen and freeze-dried to give an off-white solid, which wascharacterized infra as crystalline Form I of nicotinic acid ribosidetriacetate (NARTA) without further purification. In a glass pressuretube, the crude was suspended into methanol, and ammonia gas was bubbledinto the solution for five minutes with the temperature held at −78° C.The tube was then sealed and stored at −20° C. for 4 days, after whichthe solution was concentrated under reduced pressure. The crude was thenresolubilized into methanol and an equivalent volume of acetone wasadded, causing a phase separation to occur. The precipitate was thenfiltered under reduced pressure and washed an additional five times withcold methanol to yield nicotinic acid riboside (Compound 4) as afree-flowing orange powder in 74% yield.

¹H NMR (400 MHz, D₂O): δ ppm 9.33 (br s, 1H, aromatic), 9.02 (d, J=6.3Hz, 1H, aromatic), 8.81 (dt, J=8.0, 1.3 Hz, 1H, aromatic), 8.06 (dd,J=8.0, 6.3 Hz, 1H, aromatic), 6.09 (d, J=4.8 Hz, 1H, H-1 (anomeric)),4.37 (dd, J=4.8, 4.5 Hz, 1H, H-2), 4.33-4.36 (m, 1H, H-4), 4.23 (t,J=4.5 Hz, 1H, H-3), 3.91 (AB_(X), J_(A,A′)=12.9 Hz, J_(A,B)=3.9 Hz, 1H,H-5), 3.78 (AB_(X), J_(A,A′)=12.9 Hz, J_(A,B)=2.9 Hz, 1H, H-5′). ¹³C NMR(100 MHz, D₂O): δ ppm 167.5 (COOH), 146.9, 141.3, 140.9, 137.3, 127.9(aromatic), 99.6 (C-1 (anomeric)), 87.6 (C-4), 77.5 (C-2), 70.0 (C-3),60.4 (C-5). HRMS (ES, M+H⁺) calculated 256.0821 for C₁₁H₁₃NO₆, found256.0818.

Nicotinic acid riboside (Compound 4) was shown to be free of triflateaccording to ¹⁹F NMR, as shown in FIG. 45. Crude nicotinic acid ribosidetriacetate (NARTA) was shown to be free of triflate according to ¹⁹FNMR, as shown in FIG. 46.

The crystalline Form I of nicotinic acid riboside (NAR, Compound 4) maybe characterized by a powder X-ray diffraction pattern having peaks at19.2, 21.6, and 26.4 degrees two theta±0.2 degrees two theta. Thecrystalline Form I of nicotinic acid riboside (NAR) may also oralternatively be characterized by a powder X-ray diffraction patternhaving peaks at 15.7, 19.2, 21.6, 26.4, and 28.9 degrees two theta±0.2degrees two theta. The crystalline Form I of nicotinic acid riboside(NAR) may also or alternatively be characterized by a powder X-raydiffraction pattern having peaks at 12.8, 13.2, 15.7, 19.2, 20.5, 21.6,26.4, 28.3, 28.9 degrees two theta±0.2 degrees two theta.

In other embodiments, the crystalline Form I of nicotinic acid riboside(NAR) may be characterized by a powder X-ray diffraction patternsubstantially as shown in FIG. 17. The crystalline Form I of nicotinicacid riboside (NAR) may also or alternatively be characterized by apowder X-ray diffraction pattern having peaks substantially as providedin Table 4, below, ±0.2 degrees two theta.

TABLE 4 Peak Pos. d-spacing Height I/I_(max) No. [°2 Th.] [Å] [cts] [%]1 10.634 8.312 321 9 2 12.808 6.906 711 20 3 13.179 6.713 778 22 414.298 6.1894 387 11 5 15.669 5.651 1892 53 6 16.946 5.228 346 10 718.137 4.887 276 8 8 19.237 4.61 3542 100 9 20.548 4.3189 1233 35 1021.5597 4.1184 3298 93 11 24.019 3.702 541 15 12 25.76 3.456 150 4 1326.387 3.375 3098 87 14 27.87 3.198 165 5 15 28.3 3.151 932 26 16 28.8743.0897 1425 40 17 30.26 2.951 109 3 18 30.983 2.884 276 8 19 31.6432.8253 339 10 20 32.2 2.777 128 4 21 34.336 2.6096 602 17 22 34.9312.5665 380 11 23 35.51 2.526 118 3 24 35.9 2.4994 237 7 25 36.75 2.444148 4 26 38.53 2.335 165 5 27 39.042 2.3052 384 11 28 39.95 2.255 97 329 40.84 2.208 121 3 30 43.984 2.057 216 6 31 45.04 2.0113 101 3 3245.412 1.9956 124 4

The crystalline Form I of nicotinic acid riboside (NAR, Compound 4) mayalso or alternatively be characterized by a solid-state IR spectrumhaving peaks at 534.2, 680.8, 754.0, and 773.3 cm⁻¹±0.2 cm⁻¹. Thecrystalline Form I of nicotinic acid riboside (NAR) may also oralternatively be characterized by a solid-state IR spectrum having peaksat 534.2, 680.8, 754.0, 773.3, 1087.7, 1114.7, and 1359.6 cm⁻¹±0.2 cm⁻¹.The crystalline Form I of nicotinic acid riboside (NAR) may also oralternatively be characterized by a solid-state IR spectrum having peaksat 534.2, 680.8, 754.0, 773.3, 1087.7, 1114.7, 1359.6, 1579.4, 1612.2,and 1639.2 cm⁻¹±0.2 cm⁻¹. In certain embodiments, the crystalline Form Iof nicotinic acid riboside (NAR) may also or alternatively becharacterized by a solid-state IR spectrum substantially as shown inFIG. 23. In further embodiments, the crystalline Form I of nicotinicacid riboside (NAR) may also or alternatively be characterized by asolid-state IR spectrum having peaks substantially as provided in Table5, below, ±0.2 cm⁻¹.

TABLE 5 IR (cm⁻¹) 3257.23 3091.38 3060.53 3041.24 2950.60 1639.221612.23 1579.44 1492.66 1465.66 1359.59 1346.09 1322.95 1309.45 1267.021214.95 1182.17 1135.89 1114.67 1087.67 1052.96 979.67 948.82 923.75867.82 773.33 754.04 680.76 632.55 620.98 534.19

In another embodiment, crystalline Form I of nicotinic acid riboside(NAR) is characterized by a DSC thermogram obtained using a heating rateof 10 K/min comprising an endothermic event with an onset temperature of156° C.±2° C.

In yet another embodiment, crystalline Form I of nicotinic acid riboside(NAR) is characterized by a DSC thermogram obtained using a heating rateof 10 K/min comprising an endothermic event with a peak temperature of164° C.±2° C.

In yet another embodiment, crystalline Form I of nicotinic acid riboside(NAR) is characterized by a DSC thermogram obtained using a heating rateof 10 K/min comprising an endothermic event with an onset temperature of156° C.±2° C., a peak temperature of 164° C.±2° C., or both.

In yet another embodiment, crystalline Form I of nicotinic acid riboside(NAR) may be characterized by a DSC thermogram substantially as shown inFIG. 32.

E. Synthetic Preparation of Nicotinamide Riboside Chloride (Compound 5):Compound of Formula (Ia-H): R¹=Hydrogen, n=0, Z²=NH,R²=R³=R⁴=R⁵=R⁶=R⁷=R⁸=Hydrogen, X⁻=Chloride

To a screw setup extruder, a premix of 60 g of Compound 2 and 120 gK₂CO₃ were pre-mixed and fed at approximately 2 grams/minute (4% feedrate). The peristaltic pump was set to 1.6 mL/min, the chiller bath setto −2.5° C., and the extruder was set to 10° C. Methanol was chilled ina −80° C. freezer. The solution was quenched with 2 M aqueous HCl, thepH was brought to 6, and a sample was removed and concentrated. ¹H NMRdemonstrated complete deprotection. Additional equivalents of K₂CO₃appear advantageous for the reaction. It is expected that performing thedeprotection reaction at a higher temperature with immediate quenchingwould drive the reaction to completion.

¹H NMR (400 MHz, D₂O): δ ppm 9.46 (s, 1H, aromatic), 9.12 (dt, J=6.3,1.4 Hz, 1H, aromatic), 8.83 (dt, J=8.2, 1.4 Hz, 1H, aromatic), 8.13 (dd,J=8.2, 6.3 Hz, 1H, aromatic), 6.13 (d, J=4.3 Hz, 1H, H-1 (anomeric)),4.37 (t, J=4.7 Hz, 1H, H-2), 4.31-4.34 (m, 1H, H-4), 4.21 (t, J=4.7 Hz,1H, H-3), 3.90 (AB_(X), J_(A,A′)=13.0 Hz, J_(A,B)=3.5 Hz, 1H, H-5), 3.75(AB_(X), J_(A,A′)=13.0 Hz, J_(A,B)=2.8 Hz, 1H, H-5′). ¹³C NMR (100 MHz,D₂O): δ ppm 165.8 (C(═O)NH₂), 145.7, 142.7, 140.4, 134.0, 128.5(aromatic), 100.0 (C-1 (anomeric)), 87.8 (C-4), 77.5 (C-2), 69.9 (C-3),60.3 (C-5). HRMS (ES, M⁺) calculated 255.0981 for C₁₁H₁₅N₂O₅, found255.0986.

In other embodiments of the present invention, extruding can beperformed from about 0.5 gram/minute to about 20 grams/minute,preferably from about 0.5 grams/minute to about 10 grams/minute, mostpreferably from about 0.5 grams/minute to about 5 grams/minute.Extruding can be performed with the peristaltic pump at from about 0.25mL/min to about 10 mL/min, the chiller bath set from about −10° C. toabout 19° C., and the extruder set to from about 5° C. to about 75° C.

The reaction was repeated at room temperature with immediate quenching.To a screw setup extruder, a premix of 60 g of Compound 2 and 120 gK₂CO₃ were pre-mixed and fed at approximately 2 grams/minute (4% feedrate). The peristaltic pump was set to 2.75, the chiller bath set to 18°C., and the extruder was set to 21° C. Methanol was kept at roomtemperature. The reaction was quenched with 2 M aqueous HCl, the pH wasbrought to 6.4, and a sample was taken and concentrated. As shown inFIGS. 8 and 9, by comparison of ¹H NMR spectra of starting material andproduct, ¹H NMR demonstrated 94% conversion to Compound 5 (productmixture, middle; purified product, top), with 4% monoacetylated productand 2% nicotinamide (bottom).

A bath-based, acid-based deprotection reaction that yielded Compound 5from Compound 2 was also examined at room temperature, under both sealedmethanolic and ethanolic anhydrous acidic conditions. The acidicconditions did not require quenching, as Compound 5 crashed out ofsolution as the reaction progressed over 24 hours. However, anhydrousconditions are required in order to minimize side-product formation.Four simultaneous reactions were conducted with differing amounts of HCland MeOH or EtOH. All reactions were performed on a 5-gram scale basedon Compound 2. Conditions 1: 3 equiv. 11.65 M concentrated HCl inmethanol (3.09 mL MeOH). Conditions 2: 20 equiv. 11.65 M concentratedHCl in methanol (20.59 mL MeOH). Conditions 3: 3 equiv. 1.25 M anhydrousHCl in MeOH (28.79 mL MeOH). Conditions 4: 20 equiv. 1.25 M HCl (191.93mL MeOH). For reactions using concentrated HCl, although completedeprotection occurred, notable amounts of degradation products wereobserved after 24 hours. Using 3 equiv. 1.25 M anhydrous HCl gave thebest results with complete deprotection after 24 hours with only tracesof degradation product. Increasing to 20 equiv. anhydrous HCl onlyresulted in an increase in the amount of degradation product observed.The use of sealed tubes greatly improved the rate of reaction whencompared to open vessels. FIG. 11(a) depicts the ¹H NMR spectrum of aproduct filtrate of Compound 4. FIG. 11(b) depicts the ¹H NMR spectrumof the impurity-containing supernatant remaining after filtration ofCompound 5.

Optimized Deprotection Reactions

Reaction in Methanol: The deprotection was conducted on Compound 2 on a5-gram scale, using 3 equiv. 1.25 M anhydrous HCl in MeOH under sealedconditions. As full deprotection occurred, Compound 5 began toprecipitate out of solution. After twelve hours, the suspension in thesealed tube was filtered under reduced pressure and the cake was washedwith small volumes of EtOH. NMR of the cake (FIG. 11(a)) and of thesupernatant (FIG. 11(b)) were taken. NMR of the cake (FIG. 11(a)) showedcomplete deprotection with only trace amounts of impurities. Thesupernatant (FIG. 11(b)) is shown to contain some amount of Compound 5as well as partially deprotected material and small amounts of reactionby-products.

Reaction in Ethanol: The reaction was performed using 4 equiv. of 1.25 Manhydrous HCl in EtOH under sealed conditions. A precipitate formed asthe reaction progressed, and, after 48 hours, the suspension wasfiltered and the cake was washed with EtOH. NMR of the cake showedcomplete deprotection with only trace amounts of impurities. Thesupernatant was shown to contain some amount of Compound 5, as well aspartially deprotected material and small amounts of reactionby-products.

Reaction with in situ Generation of HCl in Ethanol: The deprotectionreaction was attempted using 4 equiv. AcCl in EtOH (30 mL). Compound 2was dissolved in EtOH and the reaction cooled to −80° C. AcCl was thenadded slowly, and the reaction mixture was tube-sealed and allowed towarm to room temperature. The reaction was left to stir overnight and awhite solid had precipitated out of solution. This white solid wasfiltered and washed with EtOH, and an NMR of the white solid was taken.NMR of the cake showed almost complete deprotection, however, somepartially deprotected material and traces of by-product could bedetected.

Reaction with in situ Generation of HCl in Methanol: The deprotectionreaction was attempted using 3 equiv. of AcCl in MeOH (30 mL). Compound2 was dissolved in MeOH and the reaction cooled to −80° C. AcCl was thenadded slowly, and the reaction mixture was tube-sealed and allowed towarm to room temperature. The reaction was left to stir overnight and awhite solid had precipitated out of solution. This white solid wasfiltered and washed with EtOH, and an NMR of the white solid was taken.NMR of the cake showed complete deprotection with trace amounts ofby-product present. The filtrate was shown to contain partiallyunprotected material and other by-products.

The crystalline Form I of nicotinamide riboside chloride (NR-Cl,Compound 5) may be characterized by a powder X-ray diffraction patternhaving peaks at 15.7, 21.8, and 26.5 degrees two theta±0.2 degrees twotheta. The crystalline Form I of nicotinamide riboside chloride may alsoor alternatively be characterized by a powder X-ray diffraction patternhaving peaks at 5.2, 15.7, 21.8, 25.3, and 26.5 degrees two theta±0.2degrees two theta. The crystalline Form I of nicotinamide ribosidechloride may also or alternatively be characterized by a powder X-raydiffraction pattern having peaks at 5.2, 157.7, 18.6, 21.8, 23.5, 23.8,25.3, 26.5, and 28.1 degrees two theta±0.2 degrees two theta.

In other embodiments, the crystalline Form I of nicotinamide ribosidechloride may be characterized by a powder X-ray diffraction patternsubstantially as shown in FIG. 15. The crystalline Form I ofnicotinamide riboside chloride may also or alternatively becharacterized by a powder X-ray diffraction pattern having peakssubstantially as provided in Table 6, below, ±0.2 degrees two theta.

TABLE 6 Peak Pos. d-spacing Height I/I_(max) No. [°2 Th.] [Å] [cts] [%]1 5.152 17.14 1051 57 2 12.247 7.221 200 11 3 14.217 6.2248 141 8 415.715 5.6346 1162 63 5 18.627 4.76 513 28 6 19.44 4.562 135 7 7 20.294.372 81 4 8 21.754 4.0821 1855 100 9 21.99 4.039 317 17 10 22.19 4.003329 18 11 22.874 3.885 260 14 12 23.549 3.7740 638 34 13 23.846 3.729511 28 14 24.113 3.688 310 17 15 25.289 3.519 1083 58 16 25.887 3.439166 9 17 26.49 3.362 1105 60 18 28.067 3.1766 670 36 19 30.1 2.967 150 820 30.624 2.9169 319 17 21 31.06 2.877 147 8 22 31.579 2.8309 165 9 2333.367 2.6832 122 7 24 33.85 2.646 159 9 25 35.613 2.519 339 18 26 36.542.457 159 9 27 37.12 2.42 72 4 28 38.531 2.3346 94 5 29 39.202 2.2962 704 30 39.774 2.2645 97 5 31 40.64 2.218 140 8 32 42.2 2.14 85 5 33 42.822.1101 111 6 34 44.62 2.029 117 6 35 45.86 1.977 148 8 36 46.69 1.943948 3 37 47.91 1.897 38 2

Preparation of Crystalline NR Methanolate Form II of NicotinamideRiboside Chloride (NR-Cl, Compound 5)

Nicotinamide riboside chloride (NR-Cl, Compound 5) was dissolved in amixture of methanol and water in a 95:5 weight:weight ratio such thatapproximately 15% of the Compound 5 was dissolved in the solventmixture. The slurry was stirred as it was heated to 50° C., until all ofthe solids dissolved. The solution was cooled to −10° C. with stirring,and crystalline NR methanolate Form II of Compound 5 precipitated fromthe solution. The crystalline NR methanolate Form II of Compound 5 andcold methanol and water were filtered to collect the crystalline NRmethanolate Form II of Compound 5. The crystalline NR methanolate FormII of Compound 5 (NR-Cl) was dried under vacuum overnight at roomtemperature.

Crystalline NR methanolate Form II of nicotinamide riboside chloride maybe characterized by a powder X-ray diffraction pattern having peaks at23.7, 24.5, and 25.4 degrees two theta±0.2 degrees two theta. Thecrystalline NR methanolate Form II of nicotinamide riboside chloride mayalso or alternatively be characterized by a powder X-ray diffractionpattern having peaks at 12.9, 23.7, 24.5, and 25.4 degrees two theta±0.2degrees two theta. The crystalline NR methanolate Form II ofnicotinamide riboside chloride may also or alternatively becharacterized by a powder X-ray diffraction pattern having peaks at12.9, 13.9, 14.8, 23.7, 24.5, and 25.4 degrees two theta±0.2 degrees twotheta.

In other embodiments, the crystalline NR methanolate Form II ofnicotinamide riboside chloride may be characterized by a powder X-raydiffraction pattern substantially as shown in FIG. 16. The crystallineNR methanolate Form II may also or alternatively be characterized by apowder X-ray diffraction pattern having peaks substantially as providedin Table 7, below, ±0.2 degrees two theta.

TABLE 7 Peak Pos. d-spacing Height I/I_(max) No. [°2 Th.] [Å] [cts] [%]1 12.938 6.837 686 35 2 13.891 6.3701 590 30 3 14.766 5.994 383 20 416.722 5.297 67 3 5 18.14 4.886 262 14 6 19.49 4.552 130 7 7 21.22 4.184292 15 8 22.54 3.942 160 8 9 22.994 3.8646 346 18 10 23.736 3.7456 110257 11 24.475 3.634 1936 100 12 25.384 3.5059 769 40 13 27.19 3.277 115 614 29.79 2.996 142 7 15 31.46 2.841 222 11 16 35.93 2.497 79 4 17 38.912.313 85 4

The crystalline NR methanolate Form II may also or alternatively becharacterized by a solid-state IR spectrum having peaks at 565.1, 611.3,638.3, and 680.8 cm⁻¹±0.2 cm⁻¹. The crystalline NR methanolate Form IImay also or alternatively be characterized by a solid-state IR spectrumhaving peaks at 565.1, 611.3, 638.3, 680.8, 981.6, 1004.8, 1026.0,1060.7, 1078.0, and 1097.3 cm⁻¹±0.2 cm⁻¹. The crystalline NR methanolateForm II may also or alternatively be characterized by a solid-state IRspectrum having peaks at 565.1, 611.3, 638.3, 680.8, 981.6, 1004.8,1026.0, 1060.7, 1078.0, 1097.3, 1400.1, 1621.9, 1648.9, and 1700.9cm⁻¹±0.2 cm⁻¹. In certain embodiments, the crystalline NR methanolateForm II may also or alternatively be characterized by a solid-state IRspectrum substantially as shown in FIG. 22. In further embodiments, thecrystalline NR methanolate Form II may be characterized by a solid-stateIR spectrum having peaks substantially as provided in Table 8, below,±0.2 cm⁻¹.

TABLE 8 IR (cm⁻¹) 3307.38 3172.38 3089.46 3068.24 2966.03 2942.892892.75 1700.94 1648.87 1621.87 1498.44 1465.66 1400.09 1311.38 1286.311263.17 1178.31 1124.32 1097.32 1078.03 1060.67 1025.96 1004.75 981.61935.32 906.39 887.11 844.68 769.47 752.11 709.69 680.76 638.33 611.33565.05

In another embodiment, crystalline NR methanolate Form II ofnicotinamide riboside chloride is characterized by a DSC thermogramobtained using a heating rate of 10 K/min comprising an endothermicevent with an onset temperature of 125° C.±2° C.

In yet another embodiment, crystalline NR methanolate Form II ofnicotinamide riboside chloride is characterized by a DSC thermogramobtained using a heating rate of 10 K/min comprising an endothermicevent with a peak temperature of 132° C.±2° C.

In yet another embodiment, crystalline NR methanolate Form II ofnicotinamide riboside chloride is characterized by a DSC thermogramobtained using a heating rate of 10 K/min comprising an onsettemperature of 125° C.±2° C., an endothermic event with a peaktemperature of 132° C.±2° C., or both.

In yet another embodiment, crystalline NR methanolate Form II ofnicotinamide riboside chloride may be characterized by a DSC thermogramsubstantially as shown in FIG. 30.

Characterization Data for Nicotinic Acid Riboside Triacetate (NARTA)

¹H NMR (D₂O, 400 MHz): δ ppm 9.28 (s, 1H, aromatic), 8.98 (d, J=6.1 Hz,1H, aromatic), 8.83 (d, J=7.8 Hz, 1H, aromatic), 8.06 (dd, J=7.8, 6.1Hz, 1H, aromatic), 6.46 (d, J=3.7 Hz, 1H, H-1 (anomeric)), 5.46 (t,J=4.7 Hz, 1H, H-3), 5.37 (t, J=5.4 Hz, 1H, H-2), 4.77-4.80 (m, 1H, H-4),4.41-4.44 (m, 2H, H-5), 2.05 (s, 3H, OAc), 2.03 (s, 3H, OAc), 1.99 (s,3H, OAc). ¹³C NMR (D₂O, 100 MHz): δ ppm 176.7, 173.5, 172.5, 164.6(3×C(═O)CH₃, COOH), 148.4, 143.7, 141.7, 133.0, 128.8 (aromatic), 97.4(C-1 (anomeric)), 82.3 (C-3), 76.6 (C-2), 69.7 (C-5), 62.8 (C-4), 20.3(s, OAc), 20.0 (s, OAc), 19.9 (s, OAc).

Crystalline Form I of Nicotinic Acid Riboside Triacetate (NARTA)

Crystalline Form I of nicotinic acid riboside triacetate (NARTA) may becharacterized by a powder X-ray diffraction pattern having peaks at 4.7,9.5, and 20.5 degrees two theta±0.2 degrees two theta. The crystallineForm I of nicotinic acid riboside triacetate (NARTA) may also oralternatively be characterized by a powder X-ray diffraction patternhaving peaks at 4.7, 9.5, 16.5, 16.8, and 20.5 degrees two theta±0.2degrees two theta. The crystalline Form I of nicotinic acid ribosidetriacetate (NARTA) may also or alternatively be characterized by apowder X-ray diffraction pattern having peaks at 4.7, 9.5, 12.0, 16.5,16.8, 19.9, 20.5, 23.7, and 23.9 degrees two theta±0.2 degrees twotheta.

In other embodiments, the crystalline Form I of nicotinic acid ribosidetriacetate (NARTA) may be characterized by a powder X-ray diffractionpattern substantially as shown in FIG. 19. The crystalline Form I ofnicotinic acid riboside triacetate (NARTA) may also or alternatively becharacterized by a powder X-ray diffraction pattern having peakssubstantially as provided in Table 9, below, ±0.2 degrees two theta.

TABLE 9 Peak Pos. d-spacing Height I/I_(max) No. [°2 Th.] [Å] [cts] [%]1 4.715 18.725 2365 90 2 8.195 10.78 357 14 3 9.464 9.338 1819 69 412.039 7.346 608 23 5 12.552 7.046 383 15 6 13.787 6.418 140 5 7 14.236.219 502 19 8 14.58 6.07 168 6 9 16.486 5.373 848 32 10 16.763 5.2851337 51 11 17.157 5.164 357 14 12 18.079 4.903 313 12 13 19.04 4.658 1144 14 19.886 4.4612 573 22 15 20.476 4.3339 2636 100 16 23.69 3.7527 68326 17 23.883 3.7228 653 25 18 24.45 3.638 164 6 19 25.724 3.4604 217 820 26.653 3.342 333 13 21 27.739 3.2134 299 11 22 28.82 3.095 191 7 2330.03 29.73 196 7 24 31.324 2.8533 167 6 25 33.62 2.663 136 5 26 34.782.578 100 4 27 26.736 2.4445 81 3

The crystalline Form I of nicotinic acid riboside triacetate (NARTA) mayalso or alternatively be characterized by a solid-state IR spectrumhaving peaks at 603.6, 684.6, 763.7, and 781.0 cm⁻¹±0.2 cm⁻¹. Thecrystalline Form I of nicotinic acid riboside triacetate (NARTA) mayalso or alternatively be characterized by a solid-state IR spectrumhaving peaks at 603.6, 684.6, 763.7, 781.0, 858.2, 894.8, 921.8, 1026.0,1051.0, and 1066.5 cm⁻¹±0.2 cm⁻¹. The crystalline Form I of nicotinicacid riboside triacetate (NARTA) may also or alternatively becharacterized by a solid-state IR spectrum having peaks at 603.6, 684.6,763.7, 781.0, 858.2, 894.8, 921.8, 1026.0, 1051.0, 1066.5, 1610.3,1639.2, and 1743.4 cm⁻¹±0.2 cm⁻¹. In certain embodiments, thecrystalline Form I of nicotinic acid riboside triacetate (NARTA) may becharacterized by a solid-state IR spectrum substantially as shown inFIG. 25. In further embodiments, the crystalline Form I of nicotinicacid riboside triacetate (NARTA) may be characterized by a solid-stateIR spectrum having peaks substantially as provided in Table 10, below,±0.2 cm⁻¹.

TABLE 10 IR (cm⁻¹) 3064.38 3041.24 2954.46 1743.36 1639.22 1610.301346.09 1226.53 1110.82 1097.32 1066.46 1051.03 1025.96 921.82 894.82858.18 781.04 763.69 684.62 603.62

In another embodiment, crystalline Form I of nicotinic acid ribosidetriacetate (NARTA) is characterized by a DSC thermogram obtained using aheating rate of 10 K/min comprising an endothermic event with an onsettemperature of 148° C.±2° C.

In yet another embodiment, crystalline Form I of nicotinic acid ribosidetriacetate (NARTA) is characterized by a DSC thermogram obtained using aheating rate of 10 K/min comprising an endothermic event with a peaktemperature of 152° C.±2° C.

In yet another embodiment, crystalline Form I of nicotinic acid ribosidetriacetate (NARTA) is characterized by a DSC thermogram obtained using aheating rate of 10 K/min comprising an endothermic event with an onsettemperature of 148° C.±2° C., a peak temperature of 152° C.±2° C., orboth.

In yet another embodiment, crystalline Form I of nicotinic acid ribosidetriacetate (NARTA) is characterized by a DSC thermogram substantially asshown in FIG. 33.

Example 2 A. Synthetic Preparation of Nicotinamide Mononucleotide(Compound 6): Compound of Formula (IIa): R¹=Hydrogen, n=0, Z²=NH,R²=R³=R⁴=R⁵=R⁷=R⁸=Y¹=Y²=Hydrogen, Y³=Oxygen

The reaction to produce Compound 6 by extrusion was performed on theThermoFisher twin screw extruder 11 mm, using a feed rate of 10 g/minwith a 1:4 ratio of nicotinamide riboside to POCl₃. The extruder came toa grinding halt as it was difficult to control the feed rate of POCl₃.The machine was opened and samples were removed from mixing zone 1 andmixing zone 2 and submitted for NMR analysis. Mixing zone 1 showed thematerial to be slightly charred but conversion to Compound 6 wasobserved, along with the presence of by-products. Mixing zone 2 did notappear to show any charring. NMR showed approximately 46% conversion toCompound 6, along with the presence of by-products. The extruder wascleaned to clear the mixing zone from the hardened material that hadformed in order to prevent torque on the screw, and a second run wasattempted.

Run 2 was performed using a feed rate of 7 g/min with a 1:3 ratio ofnicotinamide riboside to POCl₃. Once again, after the machine came to ahalt, the machine was opened and samples were removed from mixing zone 1and mixing zone 2 and submitted for NMR analysis. Mixing zone 1 showedapproximately 30% conversion to Compound 6 with no evidence of apparentdarkening of the mixture by observation. Mixing zone 2 showedapproximately 15% conversion to Compound 6. A sample of the materialthat came out of the extruder showed approximately 6% conversion toCompound 6 by NMR.

¹H NMR (D₂O, 400 MHz): δ ppm 9.32 (s, 1H, aromatic), 9.13 (m, 1H,aromatic), 8.89 (dt, J=8.0, 1.3 Hz, 1H, aromatic), 8.19 (dd, J=8.0, 6.5Hz, 1H, aromatic), 6.04 (d, J=5.5 Hz, 1H, H-1 (anomeric)), 4.54 (m, 1H,H-2), 4.46 (t, J=5.1 Hz, 1H, H-3), 4.34 (dd, J=5.0, 2.5 Hz, 1H, H-4),4.21 (AB_(X), J_(A,A′)=12.0, 4.0 Hz, 1H, H-5), 4.05 (AB_(X),J_(A,B)=12.0, 4.0 Hz, 1H, H-5). ¹³C NMR (D₂O, 100 MHz): δ ppm 165.6(C(═O)NH₂), 146.0, 142.5, 139.9, 133.9, 128.5 (aromatic), 99.9 (C-1(anomeric)), 89.4 (C-4), 77.7 (C-2), 70.9 (C-3), 64.1 (C-5). ³¹P NMR(D₂O, 162 MHz): δ ppm 0.03. HRMS (ES, M+H⁺) calculated 357.0464 forC₁₁H₁₅N₂O₈PNa, found 357.0479.

An amorphous solid form of nicotinamide mononucleotide (NMN, Compound 6)may be characterized by a powder X-ray diffraction pattern having a peakat 21.2 degrees two theta±0.2 degrees two theta.

In other embodiments, the amorphous solid form of nicotinamidemononucleotide (NMN, Compound 6) may be characterized by a powder X-raydiffraction pattern substantially as shown in FIG. 21. The amorphoussolid form of nicotinamide mononucleotide (NMN, Compound 6) may becharacterized by a powder X-ray diffraction pattern having peakssubstantially as provided in Table 11, below, ±0.2 degrees two theta.

TABLE 11 Peak Pos. d-spacing Height I/I_(max) No. [°2 Th.] [Å] [cts] [%]1 21.18 4.192 288 100

The amorphous solid form of nicotinamide mononucleotide (NMN, Compound6) may also or alternatively be characterized by a solid-state IRspectrum having peaks at 632.6, 673.1, 794.5, and 916.0 cm⁻¹±0.2 cm⁻¹.The amorphous solid form of nicotinamide mononucleotide (NMN) may alsoor alternatively be characterized by a solid-state IR spectrum havingpeaks at 632.6, 673.1, 794.5, 916.0, 991.3, 1058.8, 1405.9, 1452.2,1502.3, and 1585.2 cm⁻¹±0.2 cm⁻¹. The amorphous solid form ofnicotinamide mononucleotide (NMN) may also or alternatively becharacterized by a solid-state IR spectrum having peaks at 632.6, 673.1,794.5, 916.0, 991.3, 1058.5, 1405.9, 1452.2, 1502.3, 1585.2, 1621.9,1687.4, and 1776.2 cm⁻¹±0.2 cm⁻¹. In certain embodiments, the amorphoussolid form of nicotinamide mononucleotide (NMN) may be characterized bya solid-state IR spectrum substantially as shown in FIG. 27. In furtherembodiments, the amorphous solid form of nicotinamide mononucleotide(NMN) may be characterized by a solid-state IR spectrum having peakssubstantially as provided in Table 12, below, ±0.2 cm⁻¹.

TABLE 12 IR (cm⁻¹) 3085.60 1776.15 1687.44 1621.87 1585.23 1502.301452.16 1405.88 1058.75 991.25 916.04 794.54 673.05 632.55

In another embodiment, the amorphous solid form of nicotinamidemononucleotide (NMN, Compound 6) is characterized by a DSC thermogramobtained using a heating rate of 10 K/min comprising an endothermicevent with a peak temperature of 164° C.±2° C.

In yet another embodiment, the amorphous solid form of nicotinamidemononucleotide (NMN) is characterized by a DSC thermogram substantiallyas shown in FIG. 34.

Preparation of Crystalline Form III of Nicotinamide Mononucleotide (NMN,Compound 6)

An amorphous solid form of nicotinamide mononucleotide (NMN, Compound 6)was added to a mixture of methanol and water in a 3:2 volume:volumeratio at room temperature in an amount of nicotinamide mononucleotide(NMN) of about 200 mg per milliliter of methanol-water mixture so as todissolve the nicotinamide mononucleotide (NMN) in the methanol-watermixture. The solution of nicotinamide mononucleotide was filtered toremove any undissolved solids, and the solution was then diluted with avolume of acetone about 2 to about 5 times the total volume of methanoland water. The solution was cooled at −20° C. for two hours. Theprecipitated solid crystalline Form III of nicotinamide mononucleotide(NMN) was collected via filtration and dried overnight at roomtemperature.

Alternatively, an amorphous solid form of nicotinamide mononucleotide(NMN, Compound 6) was added to a mixture of methanol and water in a 3:2volume:volume ratio at room temperature in an amount of nicotinamidemononucleotide (NMN) of about 200 mg per milliliter of methanol-watermixture so as to dissolve the nicotinamide mononucleotide (NMN) in themethanol-water mixture. The solution of nicotinamide mononucleotide wasfiltered to remove any undissolved solids, and the solution was thencooled at −20° C. for two hours. The methanol-water mixture was thendecanted from the oily layer at the bottom of the solution. The oilylayer was left to sit overnight at room temperature to crystallize intocrystalline Form III of nicotinamide mononucleotide (NMN) and dry.

The crystalline Form III of nicotinamide mononucleotide (NMN, Compound6) may be characterized by a powder X-ray diffraction pattern havingpeaks at 7.9, 22.9, and 24.8 degrees two theta±0.2 degrees two theta.The crystalline Form III of nicotinamide mononucleotide (NMN) may alsoor alternatively be characterized by a powder X-ray diffraction patternhaving peaks at 7.9, 15.6, 17.2, 22.9, and 24.8 degrees two theta±0.2degrees two theta. The crystalline Form III of nicotinamidemononucleotide (NMN) may also or alternatively be characterized by apowder X-ray diffraction pattern having peaks at 7.9, 15.6, 17.2, 17.9,21.3, 21.9, 22.9, 24.8, 25.2, and 28.0 degrees two theta±0.2 degrees twotheta.

In other embodiments, the crystalline Form III of nicotinamidemononucleotide (NMN) may be characterized by a powder X-ray diffractionpattern substantially as shown in FIG. 20. The crystalline Form III ofnicotinamide mononucleotide (NMN) may also or alternatively becharacterized by a powder X-ray diffraction pattern having peakssubstantially as provided in Table 13, below, ±0.2 degrees two theta.

TABLE 13 Peak Pos. d-spacing Height I/I_(max) No. [°2 Th.] [Å] [cts] [%]1 7.9191 11.1553 1983 100 2 8.732 10.12 97 5 3 13.781 6.421 78 4 415.089 5.867 286 14 5 15.645 5.6597 1045 53 6 16.36 5.412 61 3 7 17.1745.159 922 46 8 17.911 4.9484 551 28 9 20.626 4.3028 299 15 10 21.2954.1689 656 33 11 21.702 4.0918 181 9 12 21.903 4.0547 564 28 13 22.8913.8818 1462 74 14 23.542 3.776 211 11 15 23.807 3.7345 387 20 16 24.7543.5938 1831 92 17 25.187 3.533 653 33 18 26.79 3.325 282 14 19 27.9553.1891 610 31 20 28.184 3.1637 385 19 21 29.929 2.9831 269 14 22 31.2762.8576 205 10 23 33.43 2.678 112 6 24 34.92 2.567 36 2 25 36.5 2.46 1658 26 38.95 2.311 56 3 27 40.87 2.206 100 5 28 42.529 2.1239 111 6 2944.2 2.047 109 5

The crystalline Form III of nicotinamide mononucleotide (NMN, Compound6) may also or alternatively be characterized by a solid-state IRspectrum having peaks at 624.8, 626.8, 671.1, 802.3, and 906.4 cm⁻¹±0.2cm⁻¹. The crystalline Form III of nicotinamide mononucleotide (NMN) mayalso or alternatively be characterized by a solid-state IR spectrumhaving peaks at 624.8, 626.8, 671.1, 802.3, 906.4, 923.8, 952.7, 985.5,1035.6, 1078.0, 1147.5, and 1182.2 cm⁻¹±0.2 cm⁻¹. The crystalline FormIII of nicotinamide mononucleotide (NMN) may also or alternatively becharacterized by a solid-state IR spectrum having peaks at 624.8, 626.8,671.1, 802.3, 906.4, 923.8, 952.7, 985.5, 1035.6, 1078.0, 1147.5,1182.2, 1409.7, 1619.9, and 1689.4 cm⁻¹±0.2 cm⁻¹. In certainembodiments, the crystalline Form III of nicotinamide mononucleotide(NMN) may be characterized by a solid-state IR spectrum substantially asshown in FIG. 26. In further embodiments, the crystalline Form III ofnicotinamide mononucleotide (NMN) may be characterized by a solid-stateIR spectrum having peaks substantially as provided in Table 14, below,±0.2 cm⁻¹.

TABLE 14 IR (cm⁻¹) 3133.81 3091.38 1689.37 1619.94 1583.30 1504.231454.09 1409.73 1373.09 1342.24 1220.74 1182.17 1147.46 1078.03 1035.60985.46 952.68 923.75 906.39 802.26 671.12 626.76 624.83

In another embodiment, crystalline Form III of nicotinamidemononucleotide (NMN, Compound 6) is characterized by a DSC thermogramobtained using a heating rate of 10 K/min comprising an endothermicevent with an onset temperature of 105° C.±2° C.

In yet another embodiment, crystalline Form III of nicotinamidemononucleotide (NMN) is characterized by a DSC thermogram obtained usinga heating rate of 10 K/min comprising an endothermic event with a peaktemperature of 157° C.±2° C.

In yet another embodiment, crystalline Form III of nicotinamidemononucleotide (NMN) is characterized by a DSC thermogram obtained usinga heating rate of 10 K/min comprising an endothermic event with an onsettemperature of 105° C.±2° C., a peak temperature of 157° C.±2° C., orboth.

In yet another embodiment, crystalline Form III of nicotinamidemononucleotide (NMN) is characterized by a DSC thermogram substantiallyas shown in FIG. 35.

Preparation of Crystalline Form IV of Nicotinamide Mononucleotide (NMN,Compound 6)

An amorphous solid form of nicotinamide mononucleotide (NMN, Compound 6)was added to a mixture of ethanol and water in a 3:2 volume:volume ratioat room temperature, in an amount of nicotinamide mononucleotide (NMN)of about 200 mg per milliliter of ethanol-water mixture so as todissolve the nicotinamide mononucleotide (NMN) in the ethanol-watermixture. The solution of nicotinamide mononucleotide was filtered toremove any undissolved solids, and the solution was then cooled at −20°C. for about 48 hours. The ethanol-water mixture was decanted from thesolid crystalline Form IV of nicotinamide mononucleotide (NMN), and thesolid crystalline Form IV of nicotinamide mononucleotide (NMN) was driedunder vacuum at room temperature overnight.

The crystalline Form IV of nicotinamide mononucleotide (NMN, Compound 6)may be characterized by a powder X-ray diffraction pattern having peaksat 9.6, 22.8, and 25.3 degrees two theta±0.2 degrees two theta. Thecrystalline Form IV of nicotinamide mononucleotide (NMN) may also oralternatively be characterized by a powder X-ray diffraction patternhaving peaks at 9.6, 16.2, 22.0, 22.8, 25.3, and 25.6 degrees twotheta±0.2 degrees two theta. The crystalline Form IV of nicotinamidemononucleotide (NMN) may also or alternatively be characterized by apowder X-ray diffraction pattern having peaks at 9.6, 16.2, 16.5, 17.4,18.9, 19.9, 22.0, 22.8, 25.3, 25.6, 27.1, and 28.7 degrees two theta±0.2degrees two theta.

In other embodiments, the crystalline Form IV of nicotinamidemononucleotide (NMN) may be characterized by a powder X-ray diffractionpattern substantially as shown in FIG. 28. The crystalline Form IV ofnicotinamide mononucleotide (NMN) may also or alternatively becharacterized by a powder X-ray diffraction pattern having peakssubstantially as provided in Table 15, below, ±0.2 degrees two theta.

TABLE 15 Peak Pos. d-spacing Height I/I_(max) No. [°2 Th.] [Å] [cts] [%]1 8.173 10.80927 268 5 2 8.924 9.90138 724 15 3 9.584 9.22091 4877 100 411.001 8.03636 108 2 5 14.677 6.03053 127 3 6 16.153 5.48262 2004 41 716.511 5.36452 1100 23 8 17.389 5.0958 1217 25 9 18.413 4.81467 740 1510 18.917 4.68751 984 20 11 19.921 4.45333 1688 35 12 22.019 4.033542526 52 13 22.831 3.89188 3232 66 14 23.174 3.83503 565 12 15 25.3013.51733 4175 86 16 25.627 3.47328 2371 49 17 25.985 3.42619 486 10 1826.35 3.37957 568 12 19 27.063 3.29219 1006 21 20 28.696 3.10844 1107 2321 29.174 3.05855 177 4 22 30.816 2.89927 646 13 23 31.776 2.8138 184 424 32.311 2.76846 85.8 2 25 33.077 2.70601 179 4 26 33.359 2.68382 136 327 34.897 2.56899 399 8 28 35.607 2.51932 96.1 2 29 36.438 2.4638 352 730 36.936 2.43167 120 2 31 37.871 2.3738 244 5 32 39.374 2.28655 350 733 40.439 2.22876 109 2 34 40.944 2.20242 87.6 2 35 42.022 2.14842 304 636 42.784 2.11187 102 2 37 43.584 2.07493 149 3 38 44.713 2.02515 132 339 45.149 2.00661 207 4 40 46.109 1.96702 140 3 41 46.617 1.94678 171 442 47.544 1.91095 61.1 1

The crystalline Form IV of nicotinamide mononucleotide (NMN) may also oralternatively be characterized by a solid-state IR spectrum having peaksat 624.8, 640.3, 665.3, 725.1, 813.8, and 840.8 cm⁻¹±0.2 cm⁻¹. Thecrystalline Form IV of nicotinamide mononucleotide (NMN) may also oralternatively be characterized by a solid-state IR spectrum having peaksat 624.8, 640.3, 665.3, 725.1, 813.8, 840.8, 867.8, 921.8, 948.8, 985.5,1029.8, and 1076.1 cm⁻¹±0.2 cm⁻¹. The crystalline Form IV ofnicotinamide mononucleotide (NMN) may also or alternatively becharacterized by a solid-state IR spectrum having peaks at 624.8, 640.3,665.3, 725.1, 813.8, 840.8, 867.8, 921.8, 948.8, 985.5, 1029.8, 1076.1,1625.7, 1646.9, and 1687.4 cm⁻¹±0.2 cm⁻¹. In certain embodiments, thecrystalline Form IV of nicotinamide mononucleotide (NMN) may becharacterized by a solid-state IR spectrum substantially as shown inFIG. 29. In further embodiments, the crystalline Form IV of nicotinamidemononucleotide (NMN) may be characterized by a solid-state IR spectrumhaving peaks substantially as provided in Table 16, below, ±0.2 cm⁻¹.

TABLE 16 IR (cm⁻¹) 3504.08 3085.60 1687.44 1646.94 1625.72 1585.231511.94 1456.02 1394.30 1238.10 1222.67 1180.24 1147.46 1139.74 1116.601095.39 1076.10 1029.82 985.46 948.82 921.82 867.82 840.83 813.83 725.12665.33 640.26 624.83

In another embodiment, crystalline Form IV of nicotinamidemononucleotide (NMN, Compound 6) is characterized by a DSC thermogramobtained using a heating rate of 10 K/min comprising an endothermicevent with an onset temperature of 144° C.±2° C.

In yet another embodiment, crystalline Form IV of nicotinamidemononucleotide (NMN) is characterized by a DSC thermogram obtained usinga heating rate of 10 K/min comprising an endothermic event with an onsettemperature of 165° C.±2° C.

In yet another embodiment, crystalline Form IV of nicotinamidemononucleotide (NMN) is characterized by a DSC thermogram obtained usinga heating rate of 10 K/min comprising an endothermic event with an onsettemperature of 144° C.±2° C., a peak temperature of 165° C.±2° C., orboth.

In yet another embodiment, crystalline Form IV of nicotinamidemononucleotide (NMN) is characterized by a DSC thermogram substantiallyas shown in FIG. 36.

It is expected through further experimentation that continuouslyprocessing a compound or derivative having formula (I), or a salt,solvate, or prodrug thereof, wherein R⁶ is hydrogen, with aphosphorylating reagent, a phosphitylating reagent, or athiophosphorylating reagent, and subsequently adding water to themixture, and adjusting the pH with an aqueous base, will effect thepreparation of a compound or derivative having formula (II), or a salt,solvate, or prodrug thereof, under almost solventless conditions. It isexpected that the compound or derivative having formula (II), or salt,solvate, or prodrug thereof, can be purified and/or isolated, and theunreacted compound or derivative having formula (I), or salt, solvate,or prodrug thereof, wherein R⁶ is hydrogen, can be separately isolated.

Example 3

It is expected that batch processing of or continuously processing acompound or derivative having formula (II), or a salt, solvate, orprodrug thereof, with a compound or derivative having formula (3), or asalt thereof, in the presence of a molar (x≤10) equivalent amount of apolar organic solvent co-reagent, and optionally in the presence ofadditional additives, then adding water to the mixture and adjusting thepH with an aqueous base, will effect the preparation of a compound orderivative having formula (III), or a salt, solvate, or prodrug thereof,under almost solventless conditions. It is expected that the compound orderivative having formula (III), or salt, solvate, or prodrug thereof,can be purified and/or isolated, and the unreacted compound orderivative having formula (II), or salt, solvate, or prodrug thereof,and the unreacted compound or derivative having formula (3), or saltthereof, can be separately isolated.

Example 4 A. Synthetic Preparation of Reduced Nicotinamide RibosideTriacetate (Compound 7): Compound of Formula (IVa): R¹=Hydrogen, n=0,Z²=NH, R²=R³=R⁴=R⁵=Hydrogen, R⁶=R⁷=R⁸=Acetyl

Nicotinamide riboside triacetate (0.500 g, 1.20 mmol, 1 eq.), sodiumdithionite (0.246 g, 1.20 mmol, 1 eq.), and sodium hydrogen carbonate(0.201 g, 2.40 mmol, 1 eq.) were added to a 35-milliliter PTFE screw-topmilling jar equipped with a 20-millimeter steel core Teflon grindingball. Water (216 μL, 12.0 mmol, 10 eq.) was added to the solids and themixture was shaken for 10 minutes in a Retsch MM400 mixer mill at 30 Hz.To the yellow suspension was added ethyl acetate (1.17 mL, 12 mmol, 10eq.), and the mixture was milled for 5 minutes at 30 Hz. The ethylacetate layer was removed from the mixture, filtered through a 0.2 mfilter, and added to a round-bottom flask for concentration. Thisprocedure was repeated once more, the organic phases were combined, andthe organic solvent was evaporated. 90 mg, 20% yield was obtained of ayellow solid, corresponding to reduced nicotinamide riboside triacetate,Compound 7.

The reduced nicotinamide riboside triacetate (NRH-TA, Compound 7) wasdissolved in ethyl acetate in an amount of NRH-TA of approximately 250mg per milliliter of ethyl acetate. Hexanes was added in a volume ofapproximately twice the volume of ethyl acetate, and the mixture wasallowed to stand for ten minutes. A layer of yellow solution wasdecanted from the top, and a dark orange oil at the bottom of the flaskwas dried under vacuum at approximately 40° C. for about 1 hour. Theresulting dried solids were grinded to a powder with mortar and pestle.

Reduced nicotinamide riboside triacetate (NRH-TA, Compound 7) wassubmitted to ¹H NMR analysis, and the structure of NRH-TA from the aboveprocedure was confirmed by comparison to a ¹H NMR experiment performedon NRH-TA as prepared using ordinary solvent-based laboratorytechniques. FIG. 41 provides a comparison of the ¹H NMR spectra ofNRH-TA as prepared using ordinary solvent-based laboratory techniques(top) with NRH-TA obtained according to the above procedure (bottom).

¹H NMR (MeOD, 400 MHz): δ ppm 7.07 (d, J=1.3 Hz, 1H, N—HC═C—C(═O)NH₂),5.95 (dq, J=8.2, 1.6 Hz, 1H, N—HC═CH), 5.16 (dd, J=5.6, 2.5 Hz, 1H,H-3), 5.11 (dd, J=7.0, 5.8 Hz, 1H, H-2), 4.95 (d, J=7.0 Hz, 1H, H-1(anomeric)), 4.79 (dt, J=8.2, 3.4 Hz, 1H, N—HC═CH), 4.11-4.21 (m, 3H,H-4, H-5, H-5′), 2.92 (dd, J=3.0, 1.5 Hz, 2H, N—HC═CH—CH ₂), 2.05 (s,3H, OAc), 2.00 (s, 3H, OAc), 1.97 (s, 3H, OAc). ¹³C NMR (MeOD, 100 MHz):δ ppm 172.9, 172.3, 171.5, 171.3 (3×O—C(═O)CH₃, C(═O)NH₂), 137.4(N—HC═C—C(═O)NH₂), 126.7 (N—HC═CH), 105.2 (N—HC═C—C(═O)NH₂), 103.6(N—HC═CH), 94.4 (C-1 (anomeric)), 80.3 (C-4), 72.1, 72.1 (C-2, C-3),64.9 (C-5), 23.7 (N—HC═CH—CH₂), 20.8, 20.5, 20.3 (3×O—C(═O)CH₃). HRMS(ES, M+H⁺) calculated 383.1454 for C₁₇H₂₃N₂O₈, found 383.1445.

In an embodiment, the amorphous form of reduced nicotinamide ribosidetriacetate (NRH-TA, Compound 7) may be characterized by a powder X-raydiffraction pattern substantially as shown in FIG. 39.

B. Synthetic Preparation of Reduced Nicotinic Acid Riboside Triacetate(Compound 8): Compound of Formula (IVa): R¹=Hydrogen, n=0, Z²=Oxygen,R²=R³=R⁴=R⁵=Hydrogen, R⁶=R⁷=R⁸=Acetyl

Nicotinic acid riboside triacetate (1.00 g, 2.40 mmol, 1 eq.), sodiumdithionite (0.492 g, 2.40 mmol, 1 eq.), and sodium hydrogen carbonate(0.403 g, 4.80 mmol, 2 eq.) were added to a 35-milliliter PTFE screw-topmilling jar equipped with a 20-millimeter steel core Teflon grindingball. Water (216 μL, 12.0 mmol, 5 eq.) was added to the solids and themixture was shaken for 10 minutes in a Retsch MM400 mixer mill at 30 Hz.To the yellow/orange suspension was added ethyl acetate (2.31 mL, 24mmol, 10 eq.), and the mixture was milled for 5 minutes at 30 Hz. Theethyl acetate layer was removed from the mixture, filtered through a 0.2m filter and added to a round-bottom flask for concentration. Thisprocedure was repeated once more, the organic phases were combined, andthe organic solvent was evaporated. 75 mg, 8.4% yield was obtained of ayellow solid, corresponding to reduced nicotinic acid ribosidetriacetate, Compound 8.

The reduced nicotinic acid riboside triacetate (NARH-TA, Compound 8) wasdissolved in ethyl acetate in an amount of NARH-TA of approximately 250mg per milliliter of ethyl acetate. Hexanes was added in a volume ofapproximately twice the volume of ethyl acetate, and the mixture wasallowed to stand for ten minutes. A layer of yellow solution wasdecanted from the top, and a dark orange oil at the bottom of the flaskwas dried under vacuum at approximately 40° C. for about 1 hour. Theresulting dried solids were grinded to a powder with mortar and pestle.

Reduced nicotinic acid riboside triacetate (NARH-TA, Compound 8) wassubmitted to ¹H NMR analysis, and the structure of NARH-TA from theabove procedure was confirmed by comparison to a ¹H NMR experimentperformed on NARH-TA as prepared using ordinary solvent-based laboratorytechniques. FIG. 42 provides a comparison of the ¹H NMR spectra ofNARH-TA as prepared using ordinary solvent-based laboratory techniques(top) with NARH-TA obtained according to the above procedure (bottom).

¹H NMR (MeOD, 400 MHz): δ ppm 7.19 (d, J=1.5 Hz, 1H, N—HC═C—COOH), 5.93(dq, J=8.3, 1.6 Hz, 1H, N—HC═CH), 5.14 (dd, J=5.6, 2.6 Hz, 1H, H-3),5.10 (dd, J=7.0, 5.8 Hz, 1H, H-2), 4.95 (d, J=7.0 Hz, 1H, H-1(anomeric)), 4.76 (dt, J=8.0, 3.5 Hz, 1H, N—HC═CH), 4.12-4.16 (m, 3H,H-4, H-5, H-5′), 2.90 (dd, J=3.0, 1.5 Hz, 2H, N—HC═CH—CH ₂), 2.03 (s,3H, OAc), 1.99 (s, 3H, OAc), 1.96 (s, 3H, OAc). ¹³C NMR (MeOD, 100 MHz):δ ppm 172.2, 171.5, 171.5, 171.3 (3×O—C(═O)CH₃, COOH), 140.0(N—HC═C—COOH), 126.8 (N—HC═CH), 106.2 (N—HC═CH), 101.6 (N—HC═C—COOH),94.2 (C-1 (anomeric)), 80.5 (C-4), 72.3, 72.2 (C-2, C-3), 64.5 (C-5),23.4 (N—HC═CH—CH₂), 20.8, 20.6, 20.4 (3×O—C(═O)CH₃). HRMS (ES, M+H⁺)calculated 384.1295 for C₁₇H₂₂NO₉, found 384.1300.

In an embodiment, the amorphous form of reduced nicotinic acid ribosidetriacetate (NARH-TA, Compound 8) may be characterized by a powder X-raydiffraction pattern substantially as shown in FIG. 40.

Thus, batch processing of or continuously processing a compound orderivative having formula (I), or a salt, solvate, or prodrug thereof,with a stoichiometric amount of a reducing agent reagent, in thepresence of a molar equivalent (1<x<10) amount of a polar solventco-reagent, then removing by-products under reduced pressure andtemperature-controlled conditions, will effect the preparation of acompound or derivative having formula (IV), or a salt, solvate, orprodrug thereof, under almost solventless conditions, i.e.,substantially free of solvent. It is expected that the compound orderivative having formula (IV), or salt, solvate, or prodrug thereof,can be purified and/or isolated, and the unreacted compound orderivative having formula (I), or salt, solvate, or prodrug thereof, canbe separately isolated.

Example 5 A. Synthetic Preparation of Reduced Nicotinamide Riboside(Compound 9): Compound of Formula (IVa-H): R¹=Hydrogen, n=0, Z²=NH,R²=R³=R⁴=R⁵=R⁶=R⁷=R⁸=Hydrogen

Reduced nicotinamide riboside triacetate (Compound 7) was deprotectedusing mechanochemical (MeOH, NaOMe) processes to remove the acetylmoieties, affording Compound 9 in quantitative yield. Compound 7 (500mg, 1.35 mmol, 1 eq.), methanol (219 μL, 5.40 mmol, 4 eq.), and NaOMe(25% in MeOH, two drops, ˜0.01 mL) were sequentially added to a35-milliliter PTFE screw-top milling jar equipped with a 20-millimetersteel core Teflon grinding ball. The mixture was shaken for 10 minutesin a Retsch MM400 mixer mill at 30 Hz. The mixture was concentrated toprovide a light brown solid in quantitative yield, corresponding toCompound 9.

The reduced nicotinamide riboside (NRH, Compound 9) was dissolved inmethanol in an amount of NRH of approximately 100 mg per milliliter ofmethanol. Isopropyl alcohol was added in a volume of approximately fivetimes the volume of methanol, the mixture was stirred for about 10minutes, and the mixture was then allowed to stand at −20° C. overnight.The majority of solvent was evaporated under high air flow over thecourse of about two hours. Solids were collected from the remainingsolvent mixture by filtering, and the solids were washed with isopropylalcohol. The solids were dried under vacuum at room temperatureovernight.

Reduced nicotinamide riboside (NRH, Compound 9) was submitted to ¹H NMRanalysis, and the structure of NRH from the above procedure wasconfirmed by comparison to a ¹H NMR experiment performed on NRH asprepared using ordinary solvent-based laboratory techniques. FIG. 43provides a comparison of the ¹H NMR spectra of NRH as prepared usingordinary solvent-based laboratory techniques (top) with NRH obtainedaccording to the above procedure (bottom).

¹H NMR (D₂O, 400 MHz): δ ppm 7.02 (d, 1H, N—HC═C—C(O)NH₂), 5.97 (dq,J=8.3, 1.5 Hz, 1H, N—HC═CH), 4.76 (dt, J=8.0, 3.5 Hz, 1H, N—HC═CH), 4.74(d, J=7.3 Hz, 1H, H-1 (anomeric)), 4.07 (dd, J=7.1, 5.5 Hz, 1H, H-2),4.00 (dd, J=5.6, 2.9 Hz, 1H, H-3), 3.82-3.85 (m, 1H, H-4), 3.61 (AB_(X),J_(A,B)=12.4 Hz, J_(A,X)=3.8 Hz, 1H, H-5), 3.55 (AB_(X), J_(A,B)=12.4Hz, J_(B,X)=4.5 Hz, 1H, H-5′), 2.94 (dd, J=3.1, 1.6 Hz, 2H, N—HC═CH—CH₂). ¹³C NMR (D₂O, 100 MHz): δ ppm 172.9 (C(═O)NH₂), 137.8(N—HC═C—C(═O)NH₂), 125.2 (N—HC═CH), 105.1 (N—HC═CH), 100.9(N—HC═C—C(═O)NH₂), 94.9 (C-1 (anomeric)), 83.5 (C-4), 70.9 (C-2), 70.1(C-3), 61.5 (C-5), 22.0 (N—HC═CH—CH₂). HRMS (ES, M+H⁺) calculated257.1137 for C₁₁H₁₇N₂O₅, found 257.1130.

In an embodiment, the amorphous form of reduced nicotinamide riboside(NRH, Compound 9) may be characterized by a powder X-ray diffractionpattern substantially as shown in FIG. 37.

B. Synthetic Preparation of Reduced Nicotinic Acid Riboside (Compound10): Compound of Formula (IVa-H): R¹=Hydrogen, n=0, Z²=Oxygen,R²=R³=R⁴=R⁵=R⁶=R⁷=R⁸=Hydrogen

Reduced nicotinic acid riboside triacetate (Compound 8) was deprotectedusing mechanochemical (MeOH, NaOMe) processes to remove the acetylmoieties, affording Compound 10 in quantitative yield. Compound 8 (500mg, 1.35 mmol, 1 eq.) and NaOMe (25% in MeOH, 340 μL, 1.49 mmol, 1.1eq.) were sequentially added to a 35-milliliter PTFE screw-top millingjar equipped with a 20-millimeter steel core Teflon grinding ball. Themixture was shaken for 10 minutes in a Retsch MM400 mixer mill at 30 Hz.The mixture was concentrated to provide an orange solid in quantitativeyield, corresponding to Compound 10.

The reduced nicotinic acid riboside (NARH, Compound 10) was dissolved inmethanol in an amount of NARH of approximately 50 mg per milliliter ofmethanol. Isopropyl alcohol was added in a volume of approximately twicethe volume of methanol. The mixture was filtered to collect theresulting solids, and the solids were vacuum dried at room temperatureovernight.

Reduced nicotinic acid riboside (NARH, Compound 10) was submitted to ¹HNMR analysis, and the structure of NARH from the above procedure wasconfirmed by comparison to a ¹H NMR experiment performed on NARH asprepared using ordinary solvent-based laboratory techniques. FIG. 44provides a comparison of the ¹H NMR spectra of NARH as prepared usingordinary solvent-based laboratory techniques (top) with NARH obtainedaccording to the above procedure (bottom).

¹H NMR (D₂O, 400 MHz): δ ppm 6.86 (br s, 1H, NHC═C—COOH), 5.91 (dq,J=8.3, 1.5 Hz, 1H, N—HC═CH), 4.76 (dt, J=8.1, 3.5 Hz, 1H, N—HC═CH), 4.74(d, J=7.0 Hz, 1H, H-1 (anomeric)), 4.05 (dd, J=6.9, 5.9 Hz, 1H, H-2),3.97 (dd, J=5.5, 3.0 Hz, 1H, H-3), 3.77-3.82 (m, 1H, H-4), 3.60 (AB_(X),J_(A,B)=12.5 Hz, J_(A,X)=3.7 Hz, 1H, H-5), 3.55 (AB_(X), J_(A,B)=12.5Hz, J_(B,X)=4.8 Hz, 1H, H-5′), 2.87 (br s, 2H, N—HC═CH—CH ₂). ¹³C NMR(D₂O, 100 MHz): δ ppm 171.1 (COOH), 136.4 (N—HC═C—COOH), 126.1(N—HC═CH), 106.1 (N—HC═C—COOH), 104.8 (N—HC═CH), 94.9 (C-1 (anomeric)),83.2 (C-4), 70.8 (C-2), 70.2 (C-3), 61.7 (C-5), 23.2 (N—HC═CH—CH₂). HRMS(ES, M+Na⁺) calculated 280.0797 for C₁₁H₁₅NO₆Na, found 280.0794.

In an embodiment, the amorphous form of reduced nicotinic acid riboside(NARH, Compound 10) may be characterized by a powder X-ray diffractionpattern substantially as shown in FIG. 38.

Thus, batch processing of or continuously processing a compound orderivative having formula (IV), or a salt, solvate, or prodrug thereof,with a molar equivalent of an alcohol and a sub-molar equivalent of aBrønsted base, will effect the preparation of a compound or derivativehaving formula (IV-H), or a salt, solvate, or prodrug thereof, underalmost solventless conditions, i.e., substantially free of solvent. Itis expected that the compound or derivative having formula (IV-H), orsalt, solvate, or prodrug thereof, can be purified and/or isolated, andthe unreacted compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, can be separately isolated.

Example 6

Acidic Hydrolysis Methodology

A jacketed reaction vessel, fitted with addition ports and agitator, wasset to 5° C. and charged with NR triacetate (NRTA) chloride (Compound 2,50 g, 120 mmol, 1.0 eq.). HCl in methanol (3 M, 160 mL, 4 eq.) wasslowly poured into the reaction vessel and stirred at a low agitation.The temperature of the solution was maintained at 5° C. and held untilthe reaction was complete, as seen by HPLC. The reaction mixture, awhite suspension, was run off and washed from the reaction vessel usingminimal methanol. The methanol suspension was filtered through a Büchnerfunnel equipped with Whatman filter paper (first isolation). Thewet-cake and mother liquor were collected and tested for acetamidecontent by GC.

Basic Hydrolysis Methodology

NR triacetate (NRTA) chloride (Compound 2, 40C081, 1240 kg) was slurriedinto methanol (2453 kg, 2.5 vols.) and chilled to ≤−10° C. Whilemaintaining the solution temperature at ≤−10° C., 30% ammonium hydroxide(248 kg) was slowly added and the reaction solution mixed untilde-acetylation was confirmed complete by HPLC. At ≤−10° C., the solutionwas placed under vacuum to strip the excess ammonia, then methyltert-butyl ether (1376 kg, 1.5 vols.) was charged to precipitate theproduct. The slurry was isolated via centrifugation at ≤−10° C. and theproduct was tested for acetamide content by GC.

Results

Hydrolysis Acetamide Sample ID Methodology (ppm) 1710-013-1 (1stisolation) Acidic ND (<5 ppm) 1710-013-1 (Mother Liquor) Acidic ND (<5ppm) Trial 1 (1st isolation) Basic 829.60 Trial 2 (1st isolation) Basic833.29 Trial 3 (1st isolation) Basic 831.36 ND = Non-detect; Basic =Basic ammonia; Acidic = HCl methodology described above; Sample IDrelates to a wet-cake unless otherwise stated.

Acetamide was not detected in the acidic deprotection in either thefiltered wet cake or the mother liquor, indicating that acetamide is notformed during the reaction. However, acetamide was detected in the basicdeprotection in three filtered wet cakes.

Example 7

It is expected that batch processing of or continuously processing acompound or derivative having formula (I), or a salt, solvate, orprodrug thereof, a stoichiometric amount of a reducing agent, and amolar equivalent (1<x<10) amount of a polar organic solvent co-reagent,then removing by-products under reduced pressure andtemperature-controlled conditions, then adding a molar equivalent of analcohol and a sub-molar equivalent of a Brønsted inorganic base andprocessing the mixture, then neutralizing the Brønsted inorganic baseusing a concentrated acid solution under controlled conditions, thenevaporating any volatile by-products, will effect the preparation of acompound or derivative having formula (IV-H), or a salt, solvate, orprodrug thereof, under almost solventless conditions, i.e.,substantially free of solvent. It is expected that the compound orderivative having formula (IV-H), or salt, solvate, or prodrug thereof,can be purified and/or isolated, and the unreacted compound orderivative having formula (I), or salt, solvate, or prodrug thereof, andthe unreacted compound or derivative having formula (IV), or salt,solvate, or prodrug thereof, can each be separately isolated.

Example 8

It is expected that batch processing of or continuously processing acompound or derivative having formula (IVb), or a salt, solvate, orprodrug thereof, with a phosphorylating reagent, or, alternatively, aphosphitylating reagent followed by an oxidizing agent reagent, or,alternatively, a thiophosphorylating reagent, then adding the mixture toiced water, then adjusting the pH of the aqueous base, will effect thepreparation of a compound or derivative having formula (V), or a salt,solvate, or prodrug thereof, under almost solventless conditions, i.e.,substantially free of solvent. It is expected that the compound orderivative having (V), or salt, solvate, or prodrug thereof, can bepurified and/or isolated, and the unreacted compound or derivativehaving formula (IVb), or salt, solvate, or prodrug thereof can beseparately isolated.

Example 9

It is expected that batch processing of or continuously processing acompound or derivative having formula (IV-H), or a salt, solvate, orprodrug thereof, with a phosphorylating reagent, or, alternatively, aphosphitylating reagent followed by an oxidizing agent reagent, or,alternatively, a thiophosphorylating reagent, then adding the mixture toiced water, then adjusting the pH of the aqueous phase with an aqueousbase, will effect the preparation of a compound or derivative havingformula (V), or a salt, solvate, or prodrug thereof, under almostsolventless conditions, i.e., substantially free of solvent. It isexpected that the compound or derivative having formula (V), or salt,solvate, or prodrug thereof, can be purified and/or isolated, and theunreacted compound or derivative having formula (IV-H), or salt,solvate, or prodrug thereof, can be separately isolated.

Example 10

It is expected that batch processing of or continuously processing acompound or derivative having formula (V), or a salt, solvate, orprodrug thereof, with a compound or derivative having formula (3), or asalt thereof, in the presence of a molar (x≤10) equivalent amount of apolar organic solvent co-reagent, and optionally in the presence ofadditional additives, then adding the mixture to iced water andadjusting the pH with an aqueous base, will effect the preparation of acompound or derivative having formula (VI), or a salt, solvate, orprodrug thereof, under almost solventless conditions, i.e.,substantially free of solvent. It is expected that the compound orderivative having formula (VI), or salt, solvate, or prodrug thereof,can be purified and/or isolated, and the unreacted compound orderivative having formula (V), or salt, solvate, or prodrug thereof, andthe unreacted compound or derivative having formula (3), or saltthereof, can each be separately isolated.

Instrumentation

X-ray powder diffraction. The X-ray powder diffraction informationconcerning the crystalline and amorphous solid forms of the compounds orderivatives prepared according to embodiments of the methods of thepresent disclosure was obtained using MiniFlex 600 Benchtop X-ray RIGAKUDiffractometer, with a Cu K-alpha 0.15418 nm X-ray tube, run in acontinuous scan mode with a scan speed of 2.0000 deg/min and a stepwidth of 0.0200 deg; the scan axis in theta/2-theta with a scan range of1.0000-50.0000 deg; and an incident slit of 1.250 deg with the receivingslit #1 set at 1.250 deg and the receiving slit #2 set at 0.3 deg.

Infrared Spectroscopy. Fourier-Transform Infrared Spectroscopy (FT-IR)spectra were obtained using a Thermo iS50 FT-IR spectrometer with adiamond Attenuated Total Reflection accessory.

Differential Scanning Calorimetry (“DSC”). DSC was conducted using aModel DSC Q20 V24.11 Differential Scanning Calorimeter at a heating rateof 10 K/min per ASTM D 3418-15. Samples were heated at 10 K/min from 20°C. to 300° C., held at 300° C., cooled to 20° C. at 10 K/min, held at20° C. for 5 minutes, then reheated to 300° C. at 10 K/min. All testingwas performed in a nitrogen environment.

It is well known that the DSC onset and peak temperatures as well asenergy values may vary due to, for example, the purity of the sample andsample size and due to instrumental parameters, especially thetemperature scan rate. Hence the DSC data presented are not to be takenas absolute values. A person skilled in the art can set up instrumentalparameters for a Differential Scanning Calorimeter so that datacomparable to the data presented here can be collected according tostandard methods, for example, those described in G. W. H. HÖHNE ET AL.,DIFFERENTIAL SCANNING CALORIMETRY (Springer 1996).

Gas chromatography (“GC”). Approximately 600 mg of each sample was addedto a 20 mL scintillation vial and exactly 10 mL of acetone was added.The samples were sonicated for 30 minutes and filtered through a 0.45 mPTFE syringe filter into a GC vial for analysis. Samples were analyzedagainst a six-point acetamide calibration curve. GC instrumentalparameters: instrument, GC with a FID; DB-FFAP column, 30.0 m×0.250mm×0.25 μm; inlet temperature, 250° C.; carrier gas flow rate, 2.0mL/min helium; split ratio, 1:1 split; FID temperature, 260° C.; runtime, 25.0 minutes; oven temperature program,

Level Rate (° C./min) Temperature (° C.) Hold (min) Initial NA  40 4.0 110 190 0.0 2 30 250 4.0Limit of detection (“LOD”), 5 ppm; Limit of quantification (“LOQ”), 10ppm.

The use of the terms “a,” “an,” “the,” and similar referents in thecontext of describing the present invention (especially in the contextof the claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein are merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range, unless otherwise indicated herein, andeach separate value is incorporated into the specification as if it wereindividually recited herein. Use of the term “about” is intended todescribe values either above or below the stated value in a range ofapproximately ±10%; in other embodiments, the values may range in valueabove or below the stated value in a range of approximately ±5%; inother embodiments, the values may range in value above or below thestated value in a range of approximately ±2%; in other embodiments, thevalues may range in value above or below the stated value in a range ofapproximately ±1%. The preceding ranges are intended to be made clear bycontext, and no further limitation is implied. All methods describedherein can be performed in any suitable order unless otherwise indicatedherein or otherwise clearly contradicted by context. The use of any andall examples, or exemplary language (e.g., “such as”) provided herein,is intended merely to better illuminate the invention and does not posea limitation on the scope of the invention unless otherwise claimed. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential to the practice of the invention.

While in the foregoing specification this invention has been describedin relation to certain embodiments thereof, and many details have beenput forth for the purpose of illustration, it will be apparent to thoseskilled in the art that the invention is susceptible to additionalembodiments and that certain of the details described herein can bevaried considerably without departing from the basic principles of theinvention.

All references cited herein are incorporated by reference in theirentireties. The present invention may be embodied in other specificforms without departing from the spirit or essential attributes thereofand, accordingly, reference should be made to the appended claims,rather than to the foregoing specification, as indicating the scope ofthe invention.

We claim:
 1. A crystalline Form I of nicotinic acid riboside (NAR)according to formula (VIII):


2. The crystalline Form I of claim 1 that is characterized by a powderX-ray diffraction pattern having peaks at 19.2, 21.6, and 26.4 degreestwo theta±0.2 degrees two theta.
 3. The crystalline Form I of claim 1that is characterized by a powder X-ray diffraction pattern having peaksat 15.7, 19.2, 21.6, 26.4, and 28.9 degrees two theta±0.2 degrees twotheta.
 4. The crystalline Form I of claim 1 that is characterized by apowder X-ray diffraction pattern having peaks substantially as shown inFIG.
 17. 5. The crystalline Form I of claim 1 that is prepared by amethod comprising the steps of: (a) dissolving the compound orderivative having formula (VIII), or a salt or solvate thereof, in avolume of methanol; (b) adding a volume of acetone, of an equal volumeto the volume of methanol, to the compound or derivative having formula(VIII), or salt or solvate thereof, in the volume of methanol; (c)precipitating the crystalline Form I; and (d) isolating the crystallineForm I.
 6. The crystalline Form I of claim 5 that is prepared by amethod further comprising the steps of: (a1) providing a compound orderivative having formula (1a), or a salt thereof:

wherein Z² is oxygen; n is 0; R¹ is hydrogen; wherein the compound orderivative having formula (1a) may optionally take the form of thecarboxylate anion conjugate base species of the compound or derivativehaving formula (1a), further optionally associated with a positivelycharged counterion selected from the group consisting of calcium,magnesium, potassium, sodium, zinc, and ammonium cations; each of R²,R³, R⁴, and R⁵ is hydrogen; (a2) treating the compound or derivativehaving formula (1a), or salt thereof, with excess trimethylsilylatingreagent(s) so as to produce a compound or derivative having formula(1a), or salt thereof, wherein R¹ is a TMS group; (a3) removing thetrimethylsilylating reagent(s); (a4) treating the compound or derivativehaving formula (1a), or salt thereof, wherein R¹ is a TMS group, with amolar equivalent amount of a compound or derivative having formula (2),or a salt thereof, and a molar equivalent amount of TMSOTf, in anorganic solvent co-reagent:

wherein X′ is selected from the group consisting of fluoro, chloro,bromo, iodo, HCO₂, acetoxy, propionoxy, butyroxy, glutamyloxy,aspartyloxy, ascorbyloxy, benzoxy, HOCO₂, citryloxy, carbamyloxy,gluconyloxy, lactyloxy, succinyloxy, sulfoxy, trifluoromethanesulfoxy,trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy;each of R⁶, R⁷, and R⁸ is —C(O)R′; R′ is methyl; (a5) processing thecompound or derivative having formula (1a), or salt thereof, wherein R¹is a TMS group, the compound or derivative having formula (2), or saltthereof, the TMSOTf, and the organic solvent co-reagent so as to producea compound or derivative having formula (Ia), or salt or solvatethereof, wherein R¹ is a TMS group; (a6) adding water to, optionally,the compound or derivative having formula (1a), or salt thereof, whereinR¹ is a TMS group, optionally, the compound or derivative having formula(2), or salt thereof, optionally the TMSOTf, the organic solventco-reagent, and the compound or derivative having formula (Ia), or saltor solvate thereof, optionally wherein R¹ is a TMS group; (a7) isolatingthe compound or derivative having formula (Ia), or salt or solvatethereof; (a8) dissolving the compound or derivative having formula (Ia),or salt or solvate thereof, in methanol, in a gas pressure tube; (a9)cooling the solution of the compound or derivative having formula (Ia),or salt or solvate thereof, in methanol, to −78° C.; (a10) bubblingammonia gas into the solution of the compound or derivative havingformula (Ia), or salt or solvate thereof, in methanol; (a11) sealing thepressure tube; (a12) raising the temperature to −20° C.; (a13) coolingthe pressure tube at −20° C. for about 12 hours to about 4 days, so asto produce the compound or derivative having formula (VIII), or salt orsolvate thereof; (a14) unsealing the gas pressure tube; and (a15)isolating the compound or derivative having formula (VIII), or salt orsolvate thereof; wherein the steps (a1) to (a15) are performedsequentially, before step (a).
 7. The crystalline Form I of claim 6,wherein the processing of step (a5) is selected from the groupconsisting of batch processing, liquid-assisted mixing, milling,grinding, and extruding.
 8. A crystalline Form I of nicotinamideriboside triacetate (NRTA) chloride according to formula (IX):


9. The crystalline Form I of claim 8 that is characterized by a powderX-ray diffraction pattern having peaks at 19.6, 22.1, and 26.6 degreestwo theta±0.2 degrees two theta.
 10. The crystalline Form I of claim 8that is characterized by a powder X-ray diffraction pattern having peaksat 9.8, 19.2, 19.6, 22.1, and 26.6 degrees two theta±0.2 degrees twotheta.
 11. The crystalline Form I of claim 8 that is characterized by apowder X-ray diffraction pattern substantially as shown in FIG.
 18. 12.The crystalline Form I of claim 8 that is prepared by a methodcomprising the steps of: (a) adding a volume of acetonitrile to thecompound or derivative having formula (IX), or a salt or solvatethereof, at room temperature, so as to dissolve the compound orderivative having formula (IX), or salt or solvate thereof, in thevolume of acetonitrile; (b) adding a volume of acetone, which is atleast equal in volume to the volume of acetonitrile, to the solution ofthe compound or derivative having formula (IX), or salt or solvatethereof, in the volume of acetonitrile so as to precipitate thecrystalline Form I; and (c) isolating the crystalline Form I.
 13. Thecrystalline Form I of claim 12 that is prepared by a method furthercomprising the steps of: (a1) providing a compound or derivative havingformula (2), or a salt thereof:

wherein X′ is selected from the group consisting of fluoro, chloro,bromo, iodo, HCO₂, acetoxy, propionoxy, butyroxy, glutamyloxy,aspartyloxy, ascorbyloxy, benzoxy, HOCO₂, citryloxy, carbamyloxy,gluconyloxy, lactyloxy, succinyloxy, sulfoxy, trifluoromethanesulfoxy,trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy;each of R⁶, R⁷, and R⁸ is —C(O)R′; R′ is methyl; (a2) treating thecompound or derivative having formula (2), or salt thereof, with a molarequivalent amount of a compound or derivative having formula (1a), or asalt thereof, and a molar equivalent amount of TMSOTf;

wherein Z² is NH; n is 0; R¹ is hydrogen; each of R², R³, R⁴, and R⁵ ishydrogen; (a3) processing the compound or derivative having formula (2),or salt thereof, the compound or derivative having formula (1a), or saltthereof, and the TMSOTf so as to produce the compound or derivativehaving formula (IX), or salt or solvate thereof; and (a4) isolating thecompound or derivative having formula (IX), or salt or solvate thereof;wherein the steps (a1) to (a4) are performed sequentially, before step(a).
 14. The crystalline Form I of claim 13, wherein the processing ofstep (a3) is selected from the group consisting of batch processing,liquid-assisted mixing, milling, grinding, and extruding.
 15. Acrystalline Form III of nicotinamide mononucleotide according to formula(XI):


16. The crystalline Form III of claim 15 that is characterized by apowder X-ray diffraction pattern having peaks at 7.9, 22.9, and 24.8degrees two theta±0.2 degrees two theta.
 17. The crystalline Form III ofclaim 15 that is characterized by a powder X-ray diffraction patternhaving peaks at 7.9, 15.6, 17.2, 22.9, and 24.8 degrees two theta±0.2degrees two theta.
 18. The crystalline Form III of claim 15 that isprepared by a method comprising the steps of: (a) adding the compound orderivative having formula (XI), or a salt or solvate thereof, to avolume of methanol and water in a 3:2 volume:volume ratio at roomtemperature; (b) stirring the compound or derivative having formula(XI), or salt or solvate thereof, and the volume of methanol and waterso as to dissolve the compound or derivative having formula (XI), orsalt or solvate thereof, in the volume of methanol and water; (c)filtering the solution of the compound or derivative having formula(XI), or salt or solvate thereof, in the volume of methanol and water,so as to remove any undissolved solids; (d) adding a volume of acetoneto the solution of the compound or derivative having formula (XI), orsalt or solvate thereof, in the volume of methanol and water, whereinthe volume of acetone is about 2 to about 5 times the combined volume ofmethanol and water; (e) cooling the compound or derivative havingformula (XI), or salt or solvate thereof, in the volume of acetone andthe volume of methanol and water, to −20° C. so as to precipitate thecrystalline Form III; (f) isolating the crystalline Form III; and (g)drying the crystalline Form III at room temperature.
 19. The crystallineForm III of claim 18 that is prepared by a method further comprising thesteps of: (a1) providing a compound or derivative having formula (Ia),or salt or solvate thereof:

wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻ isselected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate; Z² is NH; n is 0; R¹ is hydrogen; each of R², R³, R⁴,and R⁵ is hydrogen; each of R⁶, R⁷, and R⁸ is hydrogen; (a2) treatingthe compound or derivative having formula (Ia-H), or salt or solvatethereof, with a phosphorylating reagent; (a3) processing the compound orderivative having formula (Ia-H), or salt or solvate thereof, and thephosphorylating reagent, so as to produce the compound or derivativehaving formula (XI), or salt or solvate thereof; (a4) adding,optionally, the compound or derivative having formula (Ia-H), or salt orsolvate thereof, optionally, the phosphorylating reagent, and thecompound or derivative having formula (XI), or salt or solvate thereof,to iced water; and (a5) isolating the compound or derivative havingformula (XI), or salt or solvate thereof; wherein the steps (a1) to (a5)are performed sequentially, before step (a).
 20. The crystalline FormIII of claim 19, wherein the processing of step (a3) is selected fromthe group consisting of batch processing, liquid-assisted grinding, andextruding.
 21. The crystalline Form III of claim 18 that is prepared bya method further comprising the steps of: (a1) providing a compound orderivative having formula (Ia-H), or a salt or solvate thereof:

wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻ isselected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate; Z² is NH; n is 0; R¹ is hydrogen; each of R², R³, R⁴,and R⁵ is hydrogen; each of R⁶, R⁷, and R⁸ is hydrogen; (a2) treatingthe compound or derivative having formula (Ia-H), or salt or solvatethereof, with a phosphitylating reagent, and a (0<x≤20) molar equivalentamount of a Brønsted base; (a3) processing the compound or derivativehaving formula (Ia-H), or salt or solvate thereof, the phosphitylatingreagent, and the Brønsted base, so as to produce a phosphitylated analogof the compound or derivative having formula (Ia-H), or a salt orsolvate thereof; (a4) adding an oxidizing agent reagent to, optionally,the compound or derivative having formula (Ia-H), or salt or solvatethereof, optionally, the phosphitylating reagent, optionally, theBrønsted base, and the phosphitylated analog of the compound orderivative having formula (Ia-H), or salt or solvate thereof; (a5)processing the oxidizing agent reagent, optionally, the compound orderivative having formula (Ia-H), or salt or solvate thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,and the phosphitylated analog of the compound or derivative havingformula (Ia-H), or salt or solvate thereof, so as to produce thecompound or derivative having formula (XI), or salt or solvate thereof;(a6) adding, optionally, the oxidizing agent reagent, the compound orderivative having formula (Ia-H), or salt or solvate thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,optionally, the phosphitylated analog of the compound or derivativehaving formula (Ia-H), or salt or solvate thereof, and the compound orderivative having formula (XI), or salt or solvate thereof, to icedwater; and (a7) isolating the compound or derivative having formula(XI), or salt or solvate thereof; wherein the steps (a1) to (a7) areperformed sequentially before step (a).
 22. The crystalline Form III ofclaim 21, wherein the processing of steps (a3) and (a5) is eachindependently selected from the group consisting of batch processing,liquid-assisted grinding, and extruding.
 23. A crystalline Form IV ofnicotinamide mononucleotide according to formula (XI):


24. The crystalline Form IV of claim 23 that is characterized by apowder X-ray diffraction pattern having peaks at 9.6, 22.8, and 25.3degrees two theta±0.2 degrees two theta.
 25. The crystalline Form IV ofclaim 23 that is characterized by a powder X-ray diffraction patternhaving peaks at 9.6, 16.2, 22.0, 22.8, 25.3, and 25.6 degrees twotheta±0.2 degrees two theta.
 26. The crystalline Form IV of claim 23that is prepared by a method comprising the steps of: (a) adding thecompound or derivative having formula (XI), or a salt or solvatethereof, to a volume of ethanol and water in a 3:2 volume:volume ratioat room temperature, wherein the compound or derivative having formula(XI), or salt or solvate thereof, is added in an amount of about 200milligrams per milliliter of the volume of ethanol and water; (b)stirring the compound or derivative having formula (XI), or salt orsolvate thereof, and the volume of ethanol and water so as to dissolvethe compound or derivative having formula (XI), or salt or solvatethereof, in the volume of ethanol and water; (c) filtering the solutionof the compound or derivative having formula (XI), or salt or solvatethereof, in the volume of ethanol and water, so as to remove anyundissolved solids; (d) cooling the compound or derivative havingformula (XI), or salt or solvate thereof, in the volume of ethanol andwater, to −10° C. for about 48 hours so as to precipitate thecrystalline Form IV; (e) isolating the crystalline Form IV; and (f)drying the crystalline Form IV at room temperature.
 27. The crystallineForm IV of claim 26 that is prepared by a method further comprising thesteps of: (a1) providing a compound or derivative having formula (Ia-H),or a salt or solvate thereof:

wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻ isselected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate; Z² is NH; n is 0; R¹ is hydrogen; each of R², R³, R⁴,and R⁵ is hydrogen; each of R⁶, R⁷, and R⁸ is hydrogen; (a2) treatingthe compound or derivative having formula (Ia-H), or salt or solvatethereof, with a phosphorylating reagent; (a3) processing the compound orderivative having formula (Ia-H), or salt or solvate thereof, and thephosphorylating reagent, so as to produce the compound or derivativehaving formula (XI), or salt or solvate thereof; (a4) adding,optionally, the compound or derivative having formula (Ia-H), or salt orsolvate thereof, optionally, the phosphorylating reagent, and thecompound or derivative having formula (XI), or salt or solvate thereof,to iced water; and (a5) isolating the compound or derivative havingformula (XI), or salt or solvate thereof; wherein the steps (a1) to (a5)are performed sequentially, before step (a).
 28. The crystalline Form IVof claim 27, wherein the processing of step (a3) is selected from thegroup consisting of batch processing, liquid-assisted grinding, andextruding.
 29. The crystalline Form IV of claim 26 that is prepared by amethod further comprising the steps of: (a1) providing a compound orderivative having formula (Ia-H), or a salt or solvate thereof:

wherein X⁻ as counterion is absent, or when X⁻ is present, X⁻ isselected from the group consisting of fluoride, chloride, bromide,iodide, formate, acetate, propionate, butyrate, glutamate, aspartate,ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate,methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate,succinate, sulfonate, trifluoromethanesulfonate,trichloromethanesulfonate, tribromomethanesulfonate, andtrifluoroacetate; Z² is NH; n is 0; R¹ is hydrogen; each of R², R³, R⁴,and R⁵ is hydrogen; each of R⁶, R⁷, and R⁸ is hydrogen; (a2) treatingthe compound or derivative having formula (Ia-H), or salt or solvatethereof, with a phosphitylating reagent, and a (0<x≤20) molar equivalentamount of a Brønsted base; (a3) processing the compound or derivativehaving formula (Ia-H), or salt or solvate thereof, the phosphitylatingreagent, and the Brønsted base, so as to produce a phosphitylated analogof the compound or derivative having formula (Ia-H), or a salt orsolvate thereof; (a4) adding an oxidizing agent reagent to, optionally,the compound or derivative having formula (Ia-H), or salt or solvatethereof, optionally, the phosphitylating reagent, optionally, theBrønsted base, and the phosphitylated analog of the compound orderivative having formula (Ia-H), or salt or solvate thereof; (a5)processing the oxidizing agent reagent, optionally, the compound orderivative having formula (Ia-H), or salt or solvate thereof,optionally, the phosphitylating reagent, optionally, the Brønsted base,and the phosphitylated analog of the compound or derivative havingformula (Ia-H), or salt or solvate thereof, so as to produce thecompound or derivative having formula (XI), or salt or solvate thereof;(a6) adding, optionally, the oxidizing agent reagent, optionally, thecompound or derivative having formula (Ia-H), or salt or solvatethereof, optionally, the phosphitylating reagent, optionally, theBrønsted base, optionally, the phosphitylated analog of the compound orderivative having formula (Ia-H), or salt or solvate thereof, and thecompound or derivative having formula (XI), or salt or solvate thereof,to iced water; and (a7) isolating the compound or derivative havingformula (XI), or salt or solvate thereof; wherein the steps (a1) to (a7)are performed sequentially before step (a).
 30. The crystalline Form IVof claim 29, wherein the processing of steps (a3) and (a5) is eachindependently selected from the group consisting of batch processing,liquid-assisted grinding, and extruding.